Details of the Researcher

PHOTO

Gen Tamiya
Section
Graduate School of Medicine
Job title
Professor
Degree

  • 博士（理学）（名古屋大学）

  • 修士（人間・環境学）（京都大学）

Committee Memberships 2

  • 沖縄県先端医療技術実用化推進事業（バイオバンク）評価委員

    2020/12 - Present

  • 日本メディカルAI学会　理事

    2018/01 - Present

Professional Memberships 4

  • 日本メディカルAI学会

  • 日本組織適合性学会

  • 日本人類遺伝学会

  • 米国人類遺伝学会

Research Interests 7

  • 人工知能

  • 機械学習

  • ゲノム医学

  • 遺伝統計学

  • 遺伝疫学

  • 人類遺伝学

  • 遺伝学

Research Areas 4

  • Informatics / Intelligent informatics /

  • Informatics / Statistical science /

  • Life sciences / Medical biochemistry /

  • Life sciences / Genetics /

Papers 191

  1. Translational genomics of osteoarthritis in 1,962,069 individuals Peer-reviewed

    Konstantinos Hatzikotoulas, Lorraine Southam, Lilja Stefansdottir, Cindy G. Boer, Merry-Lynn McDonald, J. Patrick Pett, Young-Chan Park, Margo Tuerlings, Rick Mulders, Andrei Barysenka, Ana Luiza Arruda, Vinicius Tragante, Alison Rocco, Norbert Bittner, Shibo Chen, Susanne Horn, Vinodh Srinivasasainagendra, Ken To, Georgia Katsoula, Peter Kreitmaier, Amabel M. M. Tenghe, Arthur Gilly, Liubov Arbeeva, Lane G. Chen, Agathe M. de Pins, Daniel Dochtermann, Cecilie Henkel, Jonas Höijer, Shuji Ito, Penelope A. Lind, Bitota Lukusa-Sawalena, Aye Ko Ko Minn, Marina Mola-Caminal, Akira Narita, Chelsea Nguyen, Ene Reimann, Micah D. Silberstein, Anne-Heidi Skogholt, Hemant K. Tiwari, Michelle S. Yau, Ming Yue, Wei Zhao, Jin J. Zhou, George Alexiadis, Karina Banasik, Søren Brunak, Archie Campbell, Jackson T. S. Cheung, Joseph Dowsett, Tariq Faquih, Jessica D. Faul, Lijiang Fei, Anne Marie Fenstad, Takamitsu Funayama, Maiken E. Gabrielsen, Chinatsu Gocho, Kirill Gromov, Thomas Hansen, Georgi Hudjashov, Thorvaldur Ingvarsson, Jessica S. Johnson, Helgi Jonsson, Saori Kakehi, Juha Karjalainen, Elisa Kasbohm, Susanna Lemmelä, Kuang Lin, Xiaoxi Liu, Marieke Loef, Massimo Mangino, Daniel McCartney, Iona Y. Millwood, Joshua Richman, Mary B. Roberts, Kathleen A. Ryan, Dino Samartzis, Manu Shivakumar, Søren T. Skou, Sachiyo Sugimoto, Ken Suzuki, Hiroshi Takuwa, Maris Teder-Laving, Laurent Thomas, Kohei Tomizuka, Constance Turman, Stefan Weiss, Tian T. Wu, Eleni Zengini, Yanfei Zhang, George Babis, David A. van Heel, Bendik Winsvold, Maiken Gabrielsen, Manuel Allen Revez Ferreira, George Babis, Aris Baras, Tyler Barker, David J. Carey, Kathryn S. E. Cheah, Zhengming Chen, Jason Pui-Yin Cheung, Mark Daly, Renée de Mutsert, Charles B. Eaton, Christian Erikstrup, Ove Nord Furnes, Yvonne M. Golightly, Daniel F. Gudbjartsson, Nils P. Hailer, Caroline Hayward, Marc C. Hochberg, Georg Homuth, Laura M. Huckins, Kristian Hveem, Shiro Ikegawa, Muneaki Ishijima, Minoru Isomura, Marcus Jones, Jae H. Kang, Sharon L. R. Kardia, Margreet Kloppenburg, Peter Kraft, Nobuyuki Kumahashi, Suguru Kuwata, Ming Ta Michael Lee, Phil H. Lee, Robin Lerner, Liming Li, Steve A. Lietman, Luca Lotta, Michelle K. Lupton, Reedik Mägi, Nicholas G. Martin, Timothy E. McAlindon, Sarah E. Medland, Karl Michaëlsson, Braxton D. Mitchell, Dennis O. Mook-Kanamori, Andrew P. Morris, Toru Nabika, Fuji Nagami, Amanda E. Nelson, Sisse Rye Ostrowski, Aarno Palotie, Ole Birger Pedersen, Frits R. Rosendaal, Mika Sakurai-Yageta, Carsten Oliver Schmidt, Pak Chung Sham, Jasvinder A. Singh, Diane T. Smelser, Jennifer A. Smith, You-qiang Song, Erik Sørensen, Gen Tamiya, Yoshifumi Tamura, Chikashi Terao, Gudmar Thorleifsson, Anders Troelsen, Aspasia Tsezou, Yuji Uchio, A. G. Uitterlinden, Henrik Ullum, Ana M. Valdes, David A. van Heel, Robin G. Walters, David R. Weir, J. Mark Wilkinson, Bendik S. Winsvold, Masayuki Yamamoto, John-Anker Zwart, Kari Stefansson, Ingrid Meulenbelt, Sarah A. Teichmann, Joyce B. J. van Meurs, Unnur Styrkarsdottir, Eleftheria Zeggini

    Nature　2025/04/09

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41586-025-08771-z 　

    ISSN： 0028-0836

    eISSN： 1476-4687

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    Abstract Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes1. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide2. As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 independent associations, 513 of which have not been previously reported. Using single-cell multiomics data, we identify signal enrichment in embryonic skeletal development pathways. We integrate orthogonal lines of evidence, including transcriptome, proteome and epigenome profiles of primary joint tissues, and implicate 700 effector genes. Within these, we find rare coding-variant burden associations with effect sizes that are consistently higher than common frequency variant associations. We highlight eight biological processes in which we find convergent involvement of multiple effector genes, including the circadian clock, glial-cell-related processes and pathways with an established role in osteoarthritis (TGFβ, FGF, WNT, BMP and retinoic acid signalling, and extracellular matrix organization). We find that 10% of the effector genes express a protein that is the target of approved drugs, offering repurposing opportunities, which can accelerate translation.

  2. Profiling of runs of homozygosity from whole-genome sequence data in Japanese biobank Peer-reviewed

    Aye Ko Ko Minn, Motomichi Matsuzaki, Akira Narita, Takamitsu Funayama, Yurii Kotsar, Satoshi Makino, Jun Takayama, Tohoku Medical Megabank Project Study Group, Shinichi Kuriyama, Gen Tamiya

    Journal of Human Genetics　2025/04/03

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s10038-025-01331-3 　

    ISSN： 1434-5161

    eISSN： 1435-232X

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    Abstract Runs of homozygosity (ROHs) are widely observed across the genomes of various species and have been reported to be associated with many traits and common diseases, as well as rare recessive diseases, in human populations. Although single nucleotide polymorphism (SNP) array data have been used in previous studies on ROHs, recent advances in whole-genome sequencing (WGS) technologies and the development of nationwide cohorts/biobanks are making high-density genomic data increasingly available, and it is consequently becoming more feasible to detect ROHs at higher resolution. In the study, we searched for ROHs in two high-coverage WGS datasets from 3552 Japanese individuals and 192 three-generation families (consisting of 1120 family members) in prospective genomic cohorts. The results showed that a considerable number of ROHs, especially short ones that may have remained undetected in conventionally used SNP-array data, can be detected in the WGS data. By filtering out sequencing errors and leveraging pedigree information, longer ROHs are more likely to be detected in WGS data than in SNP-array data. Additionally, we identified gene families within ROH islands that are associated with enriched pathways related to sensory perception of taste and odors, suggesting potential signatures of selection in these key genomic regions.

  3. Sex difference in genetic risk in the prevalence of atrial fibrillation Peer-reviewed

    Sayuri TOKIOKA, Masato TAKASE, Naoki NAKAYA, Rieko HATANAKA, Kumi NAKAYA, Mana KOGURE, Ippei CHIBA, Kotaro NOCHIOKA, Hirohito METOKI, Tomohiro NAKAMURA, Mami ISHIKURO, Taku OBARA, Yohei HAMANAKA, Masatsugu ORUI, Tomoko KOBAYASHI, Akira URUNO, Eiichi N. KODAMA, Satoshi NAGAIE, Soichi OGISHIMA, Yoko IZUMI, Gen TAMIYA, Nobuo FUSE, Shinichi KURIYAMA, Satoshi YASUDA, Atsushi HOZAWA

    Heart Rhythm　2025/03/23

    Publisher: Elsevier BV

    DOI： 10.1016/j.hrthm.2025.03.1974 　

    ISSN： 1547-5271

  4. Genetic effects on gestational diabetes mellitus and their interactions with environmental factors among Japanese women Peer-reviewed

    Tomoki Kawahara, Nobutoshi Nawa, Keiko Murakami, Toshihiro Tanaka, Hisashi Ohseto, Ippei Takahashi, Akira Narita, Taku Obara, Mami Ishikuro, Masatsugu Orui, Aoi Noda, Genki Shinoda, Yuki Nagata, Satoshi Nagaie, Soichi Ogishima, Junichi Sugawara, Shigeo Kure, Kengo Kinoshita, Atsushi Hozawa, Nobuo Fuse, Gen Tamiya, Wendy L. Bennett, Margaret A. Taub, Pamela J. Surkan, Shinichi Kuriyama, Takeo Fujiwara

    Journal of Human Genetics　70　(5)　265-273　2025/03/21

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s10038-025-01330-4 　

    ISSN： 1434-5161

    eISSN： 1435-232X

  5. Genetic Risk, Healthy Lifestyle Adherence, and Risk of Developing Diabetes in the Japanese Population

    Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Akira Narita, Taku Obara, Mami Ishikuro, Akira Uruno, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Koichi Matsuda, Yoko Izumi, Kengo Kinoshita, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

    Journal of Atherosclerosis and Thrombosis　31　(12)　1717-1732　2024/12/01

    Publisher: Japan Atherosclerosis Society

    DOI： 10.5551/jat.64906 　

    ISSN： 1340-3478

    eISSN： 1880-3873

  6. Metabolomic Profiling of Open-Angle Glaucoma Etiologic Endotypes: Tohoku Multi-Omics Glaucoma Study Peer-reviewed

    Akiko Hanyuda, Yoshihiko Raita, Takahiro Ninomiya, Kazuki Hashimoto, Naoko Takada, Kota Sato, Jin Inoue, Seizo Koshiba, Gen Tamiya, Akira Narita, Masato Akiyama, Kazuko Omodaka, Satoru Tsuda, Yu Yokoyama, Noriko Himori, Yasuko Yamamoto, Takazumi Taniguchi, Kazuno Negishi, Toru Nakazawa

    Investigative Ophthalmology & Visual Science　65　(13)　44-44　2024/11/20

    Publisher: Association for Research in Vision and Ophthalmology (ARVO)

    DOI： 10.1167/iovs.65.13.44 　

    ISSN： 1552-5783

  7. Early prediction of hypertensive disorders of pregnancy toward preventive early intervention Peer-reviewed

    Satoshi Mizuno, Satoshi Nagaie, Junichi Sugawara, Gen Tamiya, Taku Obara, Mami Ishikuro, Shinichi Kuriyama, Nobuo Yaegashi, Hiroshi Tanaka, Masayuki Yamamoto, Soichi Ogishima

    AJOG Global Reports　4　(4)　100383-100383　2024/11

    Publisher: Elsevier BV

    DOI： 10.1016/j.xagr.2024.100383 　

    ISSN： 2666-5778

  8. Next-generation sequencing analysis with a population-specific human reference genome Peer-reviewed

    Tomohisa Suzuki, Kota Ninomiya, Takamitsu Funayama, Yasunobu Okamura, Shu Tadaka, Kengo Kinoshita, Masayuki Yamamoto, Shigeo Kure, Atsuo Kikuchi, Gen Tamiya, Jun Takayama

    Genes & Genetic Systems　99　2024/10/28

    Publisher: Genetics Society of Japan

    DOI： 10.1266/ggs.24-00112 　

    ISSN： 1341-7568

    eISSN： 1880-5779

  9. A Prevalent TMEM260 Deletion Causes Conotruncal Heart Defects, Including Truncus Arteriosus Peer-reviewed

    Naoya Saijo, Hisao Yaoita, Jun Takayama, Chiharu Ota, Eiichiro Kawai, Masato Kimura, Akira Ozawa, Gen Tamiya, Shigeo Kure, Atsuo Kikuchi

    American Journal of Medical Genetics Part A　197　(3)　2024/10/19

    Publisher: Wiley

    DOI： 10.1002/ajmg.a.63906 　

    ISSN： 1552-4825

    eISSN： 1552-4833

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    ABSTRACT Conotruncal heart defects are severe congenital malformations of the outflow tract, including truncus arteriosus (TA) and double‐outlet right ventricle (DORV). TA is a severe congenital heart disease (CHD) in which the main arterial outflow tract of the heart fails to separate. We recently reported TMEM260 (NM_017799.4), c.1617del (p.Trp539Cysfs*9), as a major cause of TA in the Japanese population (TMEM260 Keio‐Tohoku variant) comparable to the prevalence of the 22q11.2 deletion syndrome, which accounts for 12%–35% of TA. However, no other major causes of TA have not been identified. Here, we report a family that included a TA patient and a DORV patient, harboring the compound heterozygous variants of TMEM260, a 7066‐bp deletion encompassing exons 6–7 and c.1393C > T, p.(Gln465*). The allele frequency of the 7066‐bp deletion was particularly high in the Japanese population (0.17%). Based on the allele frequency of this deletion and c.1617del (0.36%) in the Japanese population, TMEM260 variants might be associated with more than half of the Japanese patients with TA. This study showed that TMEM260 pathogenic variants might be the most common cause of TA in the Japanese population and could explain the wide spectrum of phenotypes associated with TMEM260‐related CHD, including DORV, demonstrating the usefulness of genetic testing in Japanese patients with TA.

  10. Inconsistent embryo selection across polygenic score methods Peer-reviewed

    Shinichi Namba, Masato Akiyama, Haruka Hamanoue, Kazuto Kato, Minae Kawashima, Itaru Kushima, Koichi Matsuda, Masahiro Nakatochi, Soichi Ogishima, Kyuto Sonehara, Ken Suzuki, Atsushi Takata, Gen Tamiya, Chizu Tanikawa, Kenichi Yamamoto, Natsuko Yamamoto, Yukinori Okada, Norio Ozaki, Yukinori Okada

    Nature Human Behaviour　8　(12)　2264-2267　2024/10/14

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41562-024-02019-y 　

    eISSN： 2397-3374

  11. Comprehensive genetic analysis for identification of monogenic disorders and selection of appropriate treatments in pediatric patients with persistent thrombocytopenia Peer-reviewed

    Daichi Sato, Hinako Kirikae, Tomohiro Nakano, Saori Katayama, Hisao Yaoita, Jun Takayama, Gen Tamiya, Shigeo Kure, Atsuo Kikuchi, Yoji Sasahara

    Pediatric Hematology and Oncology　41　(8)　541-556　2024/09/24

    Publisher: Informa UK Limited

    DOI： 10.1080/08880018.2024.2395358 　

    ISSN： 0888-0018

    eISSN： 1521-0669

  12. Identification of risk loci for postpartum depression in a genome‐wide association study Peer-reviewed

    Xue Li, Nagahide Takahashi, Akira Narita, Yukako Nakamura, Mika Sakurai‐Yageta, Keiko Murakami, Mami Ishikuro, Taku Obara, Masahiro Kikuya, Fumihiko Ueno, Hirohito Metoki, Hisashi Ohseto, Ippei Takahashi, Tomohiro Nakamura, Noriko Warita, Tomoka Shoji, Zhiqian Yu, Chiaki Ono, Natsuko Kobayashi, Saya Kikuchi, Tasuku Matsuki, Fuji Nagami, Soichi Ogishima, Junichi Sugawara, Tetsuro Hoshiai, Masatoshi Saito, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Norio Ozaki, Gen Tamiya, Shinichi Kuriyama, Hiroaki Tomita

    Psychiatry and Clinical Neurosciences　78　(11)　712-720　2024/09/17

    Publisher: Wiley

    DOI： 10.1111/pcn.13731 　

    ISSN： 1323-1316

    eISSN： 1440-1819

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    Aim Genome‐wide association studies (GWAS) of postpartum depression (PPD) based on accumulated cohorts with multiple ethnic backgrounds have failed to identify significantly associated loci. Herein, we conducted a GWAS of Japanese perinatal women along with detailed confounding information to uncover PPD‐associated loci. Methods The first and second cohorts (n = 9260 and n = 8582 perinatal women enrolled in the Tohoku Medical Megabank Project) and the third cohort (n = 997), recruited at Nagoya University, underwent genotyping. Of them, 1421, 1264, and 225 were classified as PPD based on the Edinburgh Postnatal Depression Scale 1 month after delivery. The most influential confounding factors of genetic liability to PPD were selected, and logistic regression analyses were performed to evaluate genetic associations with PPD after adjusting for confounders. Results A meta‐analysis of GWAS results from the three cohorts identified significant associations between PPD and the following loci (P < 5 × 10−8) by integrating the number of deliveries and the number of family members living together as the most influential confounders: rs377546683 at DAB1, rs11940752 near UGT8, rs141172317, rs117928019, rs76631412, rs118131805 at DOCK2, rs188907279 near ZNF572, rs504378, rs690150, rs491868, rs689917, rs474978, rs690118, rs690253 near DIRAS2, rs1435984417 at ZNF618, rs57705782 near PTPRM, and rs185293917 near PDGFB. Pathway analyses indicated that SNPs suggestively associated with PPD were mostly over‐represented in categories including long‐term depression, GnRH signaling, glutamatergic synapse, oxytocin signaling, and Rap1 signaling. Conclusion The current GWAS study identified eight loci significantly associated with PPD, which may clarify the genetic structure underlying its pathogenesis.

  13. Idiopathic infantile hypercalcemia with a CYP24A1 variant triggered by vitamin D supplementation in fortified milk: A case report Peer-reviewed

    Sota Iwafuchi, Nao Uchida, Naoya Saijo, Chisumi Sogi, Miki Kamimura, Jun Takayama, Gen Tamiya, Atsuo Kikuchi, Junko Kanno

    Clinical Pediatric Endocrinology　34　(1)　60-65　2024/09/09

    Publisher: Japanese Society for Pediatric Endocrinology

    DOI： 10.1297/cpe.2024-0049 　

    ISSN： 0918-5739

    eISSN： 1347-7358

  14. Genome-wide association study based on clustering by obesity-related variables uncovers a genetic architecture of obesity in the Japanese and the UK populations Peer-reviewed

    Ippei Takahashi, Hisashi Ohseto, Fumihiko Ueno, Tomomi Oonuma, Akira Narita, Taku Obara, Mami Ishikuro, Keiko Murakami, Aoi Noda, Atsushi Hozawa, Junichi Sugawara, Gen Tamiya, Shinichi Kuriyama

    Heliyon　10　(16)　e36023-e36023　2024/08/30

    Publisher: Elsevier BV

    DOI： 10.1016/j.heliyon.2024.e36023 　

    ISSN： 2405-8440

  15. Machine learning-based reproducible prediction of type 2 diabetes subtypes Peer-reviewed

    Hayato Tanabe, Masahiro Sato, Akimitsu Miyake, Yoshinori Shimajiri, Takafumi Ojima, Akira Narita, Haruka Saito, Kenichi Tanaka, Hiroaki Masuzaki, Junichiro J. Kazama, Hideki Katagiri, Gen Tamiya, Eiryo Kawakami, Michio Shimabukuro

    Diabetologia　67　(11)　2446-2458　2024/08/21

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1007/s00125-024-06248-8 　

    ISSN： 0012-186X

    eISSN： 1432-0428

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    Abstract Aims/hypothesis Clustering-based subclassification of type 2 diabetes, which reflects pathophysiology and genetic predisposition, is a promising approach for providing personalised and effective therapeutic strategies. Ahlqvist’s classification is currently the most vigorously validated method because of its superior ability to predict diabetes complications but it does not have strong consistency over time and requires HOMA2 indices, which are not routinely available in clinical practice and standard cohort studies. We developed a machine learning (ML) model to classify individuals with type 2 diabetes into Ahlqvist’s subtypes consistently over time. Methods Cohort 1 dataset comprised 619 Japanese individuals with type 2 diabetes who were divided into training and test sets for ML models in a 7:3 ratio. Cohort 2 dataset, comprising 597 individuals with type 2 diabetes, was used for external validation. Participants were pre-labelled (T2Dkmeans) by unsupervised k-means clustering based on Ahlqvist’s variables (age at diagnosis, BMI, HbA1c, HOMA2-B and HOMA2-IR) to four subtypes: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD). We adopted 15 variables for a multiclass classification random forest (RF) algorithm to predict type 2 diabetes subtypes (T2DRF15). The proximity matrix computed by RF was visualised using a uniform manifold approximation and projection. Finally, we used a putative subset with missing insulin-related variables to test the predictive performance of the validation cohort, consistency of subtypes over time and prediction ability of diabetes complications. Results T2DRF15 demonstrated a 94% accuracy for predicting T2Dkmeans type 2 diabetes subtypes (AUCs ≥0.99 and F1 score [an indicator calculated by harmonic mean from precision and recall] ≥0.9) and retained the predictive performance in the external validation cohort (86.3%). T2DRF15 showed an accuracy of 82.9% for detecting T2Dkmeans, also in a putative subset with missing insulin-related variables, when used with an imputation algorithm. In Kaplan–Meier analysis, the diabetes clusters of T2DRF15 demonstrated distinct accumulation risks of diabetic retinopathy in SIDD and that of chronic kidney disease in SIRD during a median observation period of 11.6 (4.5–18.3) years, similarly to the subtypes using T2Dkmeans. The predictive accuracy was improved after excluding individuals with low predictive probability, who were categorised as an ‘undecidable’ cluster. T2DRF15, after excluding undecidable individuals, showed higher consistency (100% for SIDD, 68.6% for SIRD, 94.4% for MOD and 97.9% for MARD) than T2Dkmeans. Conclusions/interpretation The new ML model for predicting Ahlqvist’s subtypes of type 2 diabetes has great potential for application in clinical practice and cohort studies because it can classify individuals with missing HOMA2 indices and predict glycaemic control, diabetic complications and treatment outcomes with long-term consistency by using readily available variables. Future studies are needed to assess whether our approach is applicable to research and/or clinical practice in multiethnic populations. Graphical Abstract

  16. Genetic Risk Stratification of Primary Open-Angle Glaucoma in Japanese Individuals Peer-reviewed

    Masato Akiyama, Gen Tamiya, Kohta Fujiwara, Yukihiro Shiga, Yu Yokoyama, Kazuki Hashimoto, Masataka Sato, Kota Sato, Akira Narita, Sawako Hashimoto, Emi Ueda, Yoshihiko Furuta, Jun Hata, Masahiro Miyake, Hanako O. Ikeda, Kenji Suda, Shogo Numa, Yuki Mori, Kazuya Morino, Yusuke Murakami, Sakurako Shimokawa, Shun Nakamura, Nobuyo Yawata, Kimihiko Fujisawa, Satoshi Yamana, Kenichiro Mori, Yasuhiro Ikeda, Kazunori Miyata, Keisuke Mori, Ken Ogino, Yoshito Koyanagi, Yoichiro Kamatani, Koichi Matsuda, Yuji Yamanashi, Yoichi Furukawa, Takayuki Morisaki, Yukinori Okada, Yoshinori Murakami, Kaori Muto, Akiko Nagai, Yusuke Nakamura, Wataru Obara, Ken Yamaji, Kazuhisa Takahashi, Satoshi Asai, Yasuo Takahashi, Shinichi Higashiue, Shuzo Kobayashi, Hiroki Yamaguchi, Yasunobu Nagata, Satoshi Wakita, Chikako Nito, Yu-Ki Iwasaki, Shigeo Murayama, Kozo Yoshimori, Yoshio Miki, Daisuke Obata, Masahiko Higashiyama, Akihide Masumoto, Yoshinobu Koga, Yukihiro Koretsune, Toshiharu Ninomiya, Koh-Hei Sonoda, Toru Nakazawa, Makoto Aihara, Rei Sakata, Kenji Kashiwagi, Fumihiko Mabuchi, Kazuhide Kawase, Takeshi Iwata, Motokazu Tsujikawa, Koji M. Nishiguchi

    Ophthalmology　131　(11)　1271-1280　2024/07/17

    Publisher: Elsevier BV

    DOI： 10.1016/j.ophtha.2024.05.026 　

    ISSN： 0161-6420

  17. Associations of combined genetic and lifestyle risks with hypertension and home hypertension Peer-reviewed

    Masato Takase, Takumi Hirata, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Akira Narita, Hirohito Metoki, Michihiro Satoh, Taku Obara, Mami Ishikuro, Hisashi Ohseto, Akira Uruno, Tomoko Kobayashi, Eiichi N. Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

    Hypertension Research　47　(8)　2064-2074　2024/06/24

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41440-024-01705-8 　

    ISSN： 0916-9636

    eISSN： 1348-4214

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    Abstract No study, to our knowledge, has constructed a polygenic risk score based on clinical blood pressure and investigated the association of genetic and lifestyle risks with home hypertension. We examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. In a cross-sectional study of 7027 Japanese individuals aged ≥20 years, we developed a lifestyle score based on body mass index, alcohol consumption, physical activity, and sodium-to-potassium ratio, categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score was constructed with the target data (n = 1405) using publicly available genome-wide association study summary statistics from BioBank Japan. Using the test data (n = 5622), we evaluated polygenic risk score performance and examined the associations of combined genetic and lifestyle risks with hypertension and home hypertension. Hypertension and home hypertension were defined as blood pressure measured at a community-support center ≥140/90 mmHg or at home ≥135/85 mmHg, respectively, or self-reported treatment for hypertension. In the test data, 2294 and 2322 participants had hypertension and home hypertension, respectively. Both polygenic risk and lifestyle scores were independently associated with hypertension and home hypertension. Compared with those of participants with low genetic risk and an ideal lifestyle, the odds ratios for hypertension and home hypertension in the low genetic risk and poor lifestyle group were 1.94 (95% confidence interval, 1.34–2.80) and 2.15 (1.60–2.90), respectively. In summary, lifestyle is important to prevent hypertension; nevertheless, participants with high genetic risk should carefully monitor their blood pressure despite a healthy lifestyle.

  18. Body mass index stratification optimizes polygenic prediction of type 2 diabetes in cross-biobank analyses Peer-reviewed

    Takafumi Ojima, Shinichi Namba, Ken Suzuki, Kenichi Yamamoto, Kyuto Sonehara, Akira Narita, Yoichiro Kamatani, Gen Tamiya, Masayuki Yamamoto, Toshimasa Yamauchi, Takashi Kadowaki, Yukinori Okada

    Nature Genetics　2024/06/11

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41588-024-01782-y 　

    ISSN： 1061-4036

    eISSN： 1546-1718

  19. Long‐term clinical observation of patients with heterozygous KIF1A variants Peer-reviewed

    Aritomo Kawashima, Kaori Kodama, Yukimune Okubo, Wakaba Endo, Takehiko Inui, Miki Ikeda, Yu Katata, Noriko Togashi, Chihiro Ohba, Eri Imagawa, Kazuhiro Iwama, Takeshi Mizuguchi, Masahiro Kitami, Yu Aihara, Jun Takayama, Gen Tamiya, Atsuo Kikuchi, Shigeo Kure, Hirotomo Saitsu, Naomichi Matsumoto, Kazuhiro Haginoya

    American Journal of Medical Genetics Part A　2024/05/17

    Publisher: Wiley

    DOI： 10.1002/ajmg.a.63656 　

    ISSN： 1552-4825

    eISSN： 1552-4833

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    Abstract KIF1A‐related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long‐term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long‐term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow‐up period was 30 years (4–44 years). This long‐term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age‐related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age‐related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long‐term follow‐up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype–genotype correlation.

  20. A fine-scale genetic map of the Japanese population. International-journal Peer-reviewed

    Jun Takayama, Satoshi Makino, Takamitsu Funayama, Masao Ueki, Akira Narita, Keiko Murakami, Masatsugu Orui, Mami Ishikuro, Taku Obara, Shinichi Kuriyama, Masayuki Yamamoto, Gen Tamiya

    Clinical genetics　2024/05/08

    DOI： 10.1111/cge.14536 　

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    Genetic maps are fundamental resources for linkage and association studies. A fine-scale genetic map can be constructed by inferring historical recombination events from the genome-wide structure of linkage disequilibrium-a non-random association of alleles among loci-by using population-scale sequencing data. We constructed a fine-scale genetic map and identified recombination hotspots from 10 092 551 bi-allelic high-quality autosomal markers segregating among 150 unrelated Japanese individuals whose genotypes were determined by high-coverage (30×) whole-genome sequencing, and the genotype quality was carefully controlled by using their parents' and offspring's genotypes. The pedigree information was also utilized for haplotype phasing. The resulting genome-wide recombination rate profiles were concordant with those of the worldwide population on a broad scale, and the resolution was much improved. We identified 9487 recombination hotspots and confirmed the enrichment of previously known motifs in the hotspots. Moreover, we demonstrated that the Japanese genetic map improved the haplotype phasing and genotype imputation accuracy for the Japanese population. The construction of a population-specific genetic map will help make genetics research more accurate.

  21. Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities. International-journal Peer-reviewed

    Satoshi Narumi, Keisuke Nagasaki, Mitsuo Kiriya, Erika Uehara, Kazuhisa Akiba, Kanako Tanase-Nakao, Kazuhiro Shimura, Kiyomi Abe, Chiho Sugisawa, Tomohiro Ishii, Kenichi Miyako, Yukihiro Hasegawa, Yoshihiro Maruo, Koji Muroya, Natsuko Watanabe, Eijun Nishihara, Yuka Ito, Takahiko Kogai, Kaori Kameyama, Kazuhiko Nakabayashi, Kenichiro Hata, Maki Fukami, Hirohito Shima, Atsuo Kikuchi, Jun Takayama, Gen Tamiya, Tomonobu Hasegawa

    Nature genetics　2024/05/07

    DOI： 10.1038/s41588-024-01735-5 　

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    Insufficient thyroid hormone production in newborns is referred to as congenital hypothyroidism. Multinodular goiter (MNG), characterized by an enlarged thyroid gland with multiple nodules, is usually seen in adults and is recognized as a separate disorder from congenital hypothyroidism. Here we performed a linkage analysis of a family with both nongoitrous congenital hypothyroidism and MNG and identified a signal at 15q26.1. Follow-up analyses with whole-genome sequencing and genetic screening in congenital hypothyroidism and MNG cohorts showed that changes in a noncoding TTTG microsatellite on 15q26.1 were frequently observed in congenital hypothyroidism (137 in 989) and MNG (3 in 33) compared with controls (3 in 38,722). Characterization of the noncoding variants with epigenomic data and in vitro experiments suggested that the microsatellite is located in a thyroid-specific transcriptional repressor, and its activity is disrupted by the variants. Collectively, we presented genetic evidence linking nongoitrous congenital hypothyroidism and MNG, providing unique insights into thyroid abnormalities.

  22. Risk Factors, Prognosis, Influence on the Offspring, and Genetic Architecture of Perinatal Depression Classified Based on the Depressive Symptom Trajectory Peer-reviewed

    Hisashi Ohseto, Ippei Takahashi, Akira Narita, Taku Obara, Mami Ishikuro, Natsuko Kobayashi, Saya Kikuchi, Xue Li, Aoi Noda, Keiko Murakami, Gen Tamiya, Junichi Sugawara, Hiroaki Tomita, Shinichi Kuriyama

    Depression and Anxiety　2024　1-13　2024/03/15

    Publisher: Wiley

    DOI： 10.1155/2024/6622666 　

    ISSN： 1091-4269

    eISSN： 1520-6394

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    This study is aimed at revealing the risk factors, prognosis, influence on offspring, and genetic architecture of perinatal depression (PD) classified based on the depressive symptom trajectory. Pregnant women with no history of major depressive disorder (MDD) were recruited and followed up with their offspring from 1 to 5 years postpartum. Using four self-report questionnaires in the perinatal period, PD was classified into four subtypes: pregnancy, early postpartum, late postpartum, and chronic PD. Risk factors, depressive symptom trajectory from 1 to 5 years postpartum, and child behavior problems were compared among the four PD subtypes. Genome-wide association studies (GWASs) were conducted for each subtype. The relationships between the PD subtypes and polygenic risk scores (PRS) for MDD, a psychiatric disorder, and premenstrual syndrome (PMS), a hormonal disorder, were examined. Among 12,338 participants, 1,145 (9.3%) developed pregnancy PD, 856 (6.9%) developed early postpartum PD, 382 (3.1%) developed late postpartum PD, and 1,048 (8.5%) developed chronic PD. Depressive symptoms decreased to 61.0%–73.3% in the 5 years postpartum. The relationship between risk factors and PD varied based on the PD subtype. Additionally, chronic PD increased the risk of child behavior problems by 2- to 3-fold. The GWASs uncovered five significant variants in different loci depending on PD subtypes, suggesting a subtype-specific genetic architecture. The PRS for MDD was related to pregnancy, early postpartum, and chronic PD, while that for PMS was related to late postpartum PD. It was concluded that PD is heterogeneous depending on the depressive symptom trajectory. Thus, specific prevention and treatment strategies are needed.

  23. Development of phenotyping algorithms for hypertensive disorders of pregnancy (HDP) and their application in more than 22,000 pregnant women. International-journal Peer-reviewed

    Satoshi Mizuno, Maiko Wagata, Satoshi Nagaie, Mami Ishikuro, Taku Obara, Gen Tamiya, Shinichi Kuriyama, Hiroshi Tanaka, Nobuo Yaegashi, Masayuki Yamamoto, Junichi Sugawara, Soichi Ogishima

    Scientific reports　14　(1)　6292-6292　2024/03/15

    DOI： 10.1038/s41598-024-55914-9 　

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    Recently, many phenotyping algorithms for high-throughput cohort identification have been developed. Prospective genome cohort studies are critical resources for precision medicine, but there are many hurdles in the precise cohort identification. Consequently, it is important to develop phenotyping algorithms for cohort data collection. Hypertensive disorders of pregnancy (HDP) is a leading cause of maternal morbidity and mortality. In this study, we developed, applied, and validated rule-based phenotyping algorithms of HDP. Two phenotyping algorithms, algorithms 1 and 2, were developed according to American and Japanese guidelines, and applied into 22,452 pregnant women in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank project. To precise cohort identification, we analyzed both structured data (e.g., laboratory and physiological tests) and unstructured clinical notes. The identified subtypes of HDP were validated against reference standards. Algorithms 1 and 2 identified 7.93% and 8.08% of the subjects as having HDP, respectively, along with their HDP subtypes. Our algorithms were high performing with high positive predictive values (0.96 and 0.90 for algorithms 1 and 2, respectively). Overcoming the hurdle of precise cohort identification from large-scale cohort data collection, we achieved both developed and implemented phenotyping algorithms, and precisely identified HDP patients and their subtypes from large-scale cohort data collection.

  24. Genetic etiology of truncus arteriosus excluding 22q11.2 deletion syndrome and identification of c.1617del, a prevalent variant in TMEM260, in the Japanese population. International-journal Peer-reviewed

    Hisao Yaoita, Eiichiro Kawai, Jun Takayama, Shinya Iwasawa, Naoya Saijo, Masayuki Abiko, Kouta Suzuki, Masato Kimura, Akira Ozawa, Gen Tamiya, Shigeo Kure, Atsuo Kikuchi

    Journal of human genetics　2024/02/13

    DOI： 10.1038/s10038-024-01223-y 　

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    Truncus Arteriosus (TA) is a congenital heart disease characterized by a single common blood vessel emerging from the right and left ventricles instead of the main pulmonary artery and aorta. TA accounts for 4% of all critical congenital heart diseases. The most common cause of TA is 22q11.2 deletion syndrome, accounting for 12-35% of all TA cases. However, no major causes of TA other than 22q11.2 deletion have been reported. We performed whole-genome sequencing of 11 Japanese patients having TA without 22q11.2 deletion. Among five patients, we identified pathogenic variants in TMEM260; the biallelic loss-of-function variants of which have recently been associated with structural heart defects and renal anomalies syndrome (SHDRA). In one patient, we identified a de novo pathogenic variant in GATA6, and in another patient, we identified a de novo probably pathogenic variant in NOTCH1. Notably, we identified a prevalent variant in TMEM260 (ENST00000261556.6), c.1617del (p.Trp539Cysfs*9), in 8/22 alleles among the 11 patients. The c.1617del variant was estimated to occur approximately 23 kiloyears ago. Based on the allele frequency of the c.1617del variant in the Japanese population (0.36%), approximately 26% of Japanese patients afflicted with TA could harbor homozygous c.1617del variants. This study highlights TMEM260, especially c.1617del, as a major genetic cause of TA in the Japanese population.

  25. Treatment of ZC4H2 Variant-Associated Spastic Paraplegia with Selective Dorsal Rhizotomy and Intensive Postoperative Rehabilitation: A Case Report. Peer-reviewed

    Toshiki Inotani, Akira Horaguchi, Yuko Morishita, Ayuko Yoshida, Misaki Otomo, Makoto Suzuki, Takehiko Inui, Yukimune Okubo, Shigemasa Komatsu, Chika Mizuno, Yuko Takahashi, Tatsuhiro Ochiai, Takeshi Kinjo, Takashi Asato, Jun Takayama, Gen Tamiya, Naoya Saijo, Atsuo Kikuchi, Kazuhiro Haginoya

    The Tohoku journal of experimental medicine　2024/01/25

    DOI： 10.1620/tjem.2024.J004 　

  26. Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS). Peer-reviewed

    Sei Harada, Miho Iida, Naoko Miyagawa, Aya Hirata, Kazuyo Kuwabara, Minako Matsumoto, Tomonori Okamura, Shun Edagawa, Yoko Kawada, Atsuko Miyake, Ryota Toki, Miki Akiyama, Atsuki Kawai, Daisuke Sugiyama, Yasunori Sato, Ryo Takemura, Kota Fukai, Yoshiki Ishibashi, Suzuka Kato, Ayako Kurihara, Mizuki Sata, Takuma Shibuki, Ayano Takeuchi, Shun Kohsaka, Mitsuaki Sawano, Satoshi Shoji, Yoshikane Izawa, Masahiro Katsumata, Koichi Oki, Shinichi Takahashi, Tsubasa Takizawa, Hiroshi Maruya, Yuji Nishiwaki, Ryo Kawasaki, Akiyoshi Hirayama, Takamasa Ishikawa, Rintaro Saito, Asako Sato, Tomoyoshi Soga, Masahiro Sugimoto, Masaru Tomita, Shohei Komaki, Hideki Ohmomo, Kanako Ono, Yayoi Otsuka-Yamasaki, Atsushi Shimizu, Yoichi Sutoh, Atsushi Hozawa, Kengo Kinoshita, Seizo Koshiba, Kazuki Kumada, Soichi Ogishima, Mika Sakurai-Yageta, Gen Tamiya, Toru Takebayashi

    Journal of epidemiology　2024/01/06

    DOI： 10.2188/jea.JE20230192 　

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    The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35-74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study used an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability, functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women's health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

  27. Evaluation of AI-assisted colposcopy for detecting high-risk subtypes of human papillomavirus in CIN2 Peer-reviewed

    European Journal of Gynaecological Oncology　45　(1)　143-143　2024

    Publisher: MRE Press

    DOI： 10.22514/ejgo.2024.020 　

    ISSN： 0392-2936

  28. Case Report: Identification of a CARD8 variant in all three patients with PFAPA syndrome complicated with Kawasaki disease. International-journal Peer-reviewed

    Haruhiko Nakamura, Atsuo Kikuchi, Hideyuki Sakai, Miki Kamimura, Yohei Watanabe, Ryoichi Onuma, Jun Takayama, Gen Tamiya, Yoichi Mashimo, Ryota Ebata, Hiromichi Hamada, Tomohiro Suenaga, Yoshihiro Onouchi, Satoru Kumaki

    Frontiers in pediatrics　12　1340263-1340263　2024

    DOI： 10.3389/fped.2024.1340263 　

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    BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA syndrome), and Kawasaki disease (KD) are both considered to be disorders of the innate immune system, and the potential role of inflammasome activation in the immunopathogenesis of both diseases has been previously described. CASE PRESENTATION: Herein, we report the clinical courses of three patients who presented a rare combination of PFAPA syndrome and KD. Two patients who presented KD later developed the PFAPA syndrome, of whom one developed recurrent KD 2 years after the initial diagnosis. The third patient developed KD one year after the onset of PFAPA syndrome. The presence of both of these conditions within individual patients, combined with the knowledge that inflammasome activation is involved in both PFAPA syndrome and KD, suggests a shared background of inflammatory dysregulation. To elucidate the mechanism underlying shared inflammatory dysregulation, we investigated the roles of Nod-like receptors (NLRs) and their downstream inflammasome-related genes. All the patients had a frameshift variant in CARD8 (CARD8-FS). A previous study demonstrated a higher frequency of CARD8-FS, whose product loses CARD8 activity and activates the NLRP3 inflammasome, in patients with the PFAPA syndrome. Additionally, the NLRP3 inflammasome is known to be activated in patients with KD. Together, these results suggest that the CARD8-FS variant may also be essential in KD pathogenesis. As such, we analyzed the CARD8 variants among patients with KD. However, we found no difference in the variant frequency between patients with KD and the general Japanese population. CONCLUSIONS: We report the clinical courses of three patients with a rare combination of PFAPA syndrome and KD. All the patients had the CARD8-FS variant. However, we could not find a difference in the variant frequency between patients with KD and the general Japanese population. As the frequency of KD is much higher than that of PFAPA among Japanese patients, and the cause of KD is multifactorial, it is possible that only a small portion of patients with KD harbor CARD8-FS as a causative gene.

  29. Machine Learning of Histopathological Images Predicts Recurrences of Resected Pancreatic Ductal Adenocarcinoma With Adjuvant Treatment Peer-reviewed

    Ruri Yamaguchi, Hiromu Morikawa, Jun Akatsuka, Yasushi Numata, Aya Noguchi, Takashi Kokumai, Masaharu Ishida, Masamichi Mizuma, Kei Nakagawa, Michiaki Unno, Akimitsu Miyake, Gen Tamiya, Yoichiro Yamamoto, Toru Furukawa

    Pancreas　2023/12/21

    Publisher: Ovid Technologies (Wolters Kluwer Health)

    DOI： 10.1097/mpa.0000000000002289 　

    ISSN： 0885-3177

    eISSN： 1536-4828

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    Objectives Pancreatic ductal adenocarcinoma is an intractable disease with frequent recurrence after resection and adjuvant therapy. The present study aimed to clarify whether artificial intelligence–assisted analysis of histopathological images can predict recurrence in patients with pancreatic ductal adenocarcinoma who underwent resection and adjuvant chemotherapy with tegafur/5-chloro-2,4-dihydroxypyridine/potassium oxonate. Materials and Methods Eighty-nine patients were enrolled in the study. Machine-learning algorithms were applied to 10-billion-scale pixel data of whole-slide histopathological images to generate key features using multiple deep autoencoders. Areas under the curve were calculated from receiver operating characteristic curves using a support vector machine with key features alone and by combining with clinical data (age and carbohydrate antigen 19-9 and carcinoembryonic antigen levels) for predicting recurrence. Supervised learning with pathological annotations was conducted to determine the significant features for predicting recurrence. Results Areas under the curves obtained were 0.73 (95% confidence interval, 0.59–0.87) by the histopathological data analysis and 0.84 (95% confidence interval, 0.73–0.94) by the combinatorial analysis of histopathological data and clinical data. Supervised learning model demonstrated that poor tumor differentiation was significantly associated with recurrence. Conclusions Results indicate that machine learning with the integration of artificial intelligence–driven evaluation of histopathological images and conventional clinical data provides relevant prognostic information for patients with pancreatic ductal adenocarcinoma.

  30. jMorp: Japanese Multi-Omics Reference Panel update report 2023. International-journal Peer-reviewed

    Shu Tadaka, Junko Kawashima, Eiji Hishinuma, Sakae Saito, Yasunobu Okamura, Akihito Otsuki, Kaname Kojima, Shohei Komaki, Yuichi Aoki, Takanari Kanno, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Jun Takayama, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Ritsuko Shimizu, Masahiro Hiratsuka, Ikuko N Motoike, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

    Nucleic acids research　2023/11/01

    DOI： 10.1093/nar/gkad978 　

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    Modern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.

  31. Influence of Diabetes Family History on the Associations of Combined Genetic and Lifestyle Risks with Diabetes in the Tohoku Medical Megabank Community-Based Cohort Study. Peer-reviewed

    Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Akira Narita, Taku Obara, Mami Ishikuro, Akira Uruno, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Ichiro Tsuji, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

    Journal of atherosclerosis and thrombosis　2023/10/06

    DOI： 10.5551/jat.64425 　

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    AIM: The influence of family history of diabetes, probably reflecting genetic and lifestyle factors, on the association of combined genetic and lifestyle risks with diabetes is unknown. We examined these associations. METHODS: This cross-sectional study included 9,681 participants in the Tohoku Medical Megabank Community-based Cohort Study. A lifestyle score, which was categorized into ideal, intermediate, and poor lifestyles, was given. Family history was obtained through a self-reported questionnaire. A polygenic risk score (PRS) was constructed in the target data (n=1,936) using publicly available genome-wide association study summary statistics from BioBank Japan. For test data (n=7,745), we evaluated PRS performance and examined the associations of combined family history and genetic and lifestyle risks with diabetes. Diabetes was defined as non-fasting blood glucose ≥ 200 mmHg, HbA1c ≥ 6.5%, and/or self-reported diabetes treatment. RESULTS: In test data, 467 (6.0%) participants had diabetes. Compared with a low genetic risk and an ideal lifestyle without a family history, the odds ratio (OR) was 3.73 (95% confidence interval [CI], 1.92-7.00) for a lower genetic risk and a poor lifestyle without a family history. Family history was significantly associated with diabetes (OR, 3.58 [95% CI, 1.73-6.98]), even in those with a low genetic risk and an ideal lifestyle. Even among participants who had an ideal lifestyle without a family history, a high genetic risk was associated with diabetes (OR, 2.49 [95% CI, 1.65-3.85]). Adding PRS to family history and conventional lifestyle risk factors improved the prediction ability for diabetes. CONCLUSIONS: Our findings support the notion that a healthy lifestyle is important to prevent diabetes regardless of genetic risk.

  32. A Case Series of Patients With MYBPC1 Gene Variants Featuring Undulating Tongue Movements as Myogenic Tremor Peer-reviewed

    Saki Uneoka, Tomoko Kobayashi, Yurika Numata-Uematsu, Yoshitsugu Oikawa, Yu Katata, Yukimune Okubo, Yu Abe, Atsuo Kikuchi, Jun Takayama, Gen Tamiya, Shigeo Kure, Kayoko Saito, Mitsugu Uematsu

    Pediatric Neurology　146　16-20　2023/09

    Publisher: Elsevier BV

    DOI： 10.1016/j.pediatrneurol.2023.06.002 　

    ISSN： 0887-8994

  33. Establishment of the early prediction models of low-birth-weight reveals influential genetic and environmental factors: a prospective cohort study. International-journal Peer-reviewed

    Satoshi Mizuno, Satoshi Nagaie, Gen Tamiya, Shinichi Kuriyama, Taku Obara, Mami Ishikuro, Hiroshi Tanaka, Kengo Kinoshita, Junichi Sugawara, Masayuki Yamamoto, Nobuo Yaegashi, Soichi Ogishima

    BMC pregnancy and childbirth　23　(1)　628-628　2023/08/31

    DOI： 10.1186/s12884-023-05919-5 　

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    BACKGROUND: Low birth weight (LBW) is a leading cause of neonatal morbidity and mortality, and increases various disease risks across life stages. Prediction models of LBW have been developed before, but have limitations including small sample sizes, absence of genetic factors and no stratification of neonate into preterm and term birth groups. In this study, we challenged the development of early prediction models of LBW based on environmental and genetic factors in preterm and term birth groups, and clarified influential variables for LBW prediction. METHODS: We selected 22,711 neonates, their 21,581 mothers and 8,593 fathers from the Tohoku Medical Megabank Project Birth and Three-Generation cohort study. To establish early prediction models of LBW for preterm birth and term birth groups, we trained AI-based models using genetic and environmental factors of lifestyles. We then clarified influential environmental and genetic factors for predicting LBW in the term and preterm groups. RESULTS: We identified 2,327 (10.22%) LBW neonates consisting of 1,077 preterm births and 1,248 term births. Our early prediction models archived the area under curve 0.96 and 0.95 for term LBW and preterm LBW models, respectively. We revealed that environmental factors regarding eating habits and genetic features related to fetal growth were influential for predicting LBW in the term LBW model. On the other hand, we identified that genomic features related to toll-like receptor regulations and infection reactions are influential genetic factors for prediction in the preterm LBW model. CONCLUSIONS: We developed precise early prediction models of LBW based on lifestyle factors in the term birth group and genetic factors in the preterm birth group. Because of its accuracy and generalisability, our prediction model could contribute to risk assessment of LBW in the early stage of pregnancy and control LBW risk in the term birth group. Our prediction model could also contribute to precise prediction of LBW based on genetic factors in the preterm birth group. We then identified parental genetic and maternal environmental factors during pregnancy influencing LBW prediction, which are major targets for understanding the LBW to address serious burdens on newborns' health throughout life.

  34. Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder. International-journal Peer-reviewed

    Masaki Nishioka, Jun Takayama, Naomi Sakai, An-A Kazuno, Mizuho Ishiwata, Junko Ueda, Takashi Hayama, Kumiko Fujii, Toshiyuki Someya, Shinichi Kuriyama, Gen Tamiya, Atsushi Takata, Tadafumi Kato

    Molecular psychiatry　2023/05/30

    DOI： 10.1038/s41380-023-02096-x 　

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    Bipolar disorder (BD) is a global medical issue, afflicting around 1% of the population with manic and depressive episodes. Despite various genetic studies, the genetic architecture and pathogenesis of BD have not been fully resolved. Besides germline variants, postzygotic mosaic variants are proposed as new candidate mechanisms contributing to BD. Here, we performed extensive deep exome sequencing (DES, ~300×) and validation experiments to investigate the roles of mosaic variants in BD with 235 BD cases (194 probands of trios and 41 single cases) and 39 controls. We found an enrichment of developmental disorder (DD) genes in the genes hit by deleterious mosaic variants in BD (P = 0.000552), including a ClinVar-registered pathogenic variant in ARID2. An enrichment of deleterious mosaic variants was also observed for autism spectrum disorder (ASD) genes (P = 0.000428). The proteins coded by the DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interaction than expected, suggesting molecular mechanisms shared with DD/ASD but restricted to a subset of cells in BD. We also found significant enrichment of mitochondrial heteroplasmic variants, another class of mosaic variants, in mitochondrial tRNA genes in BD (P = 0.0102). Among them, recurrent m.3243 A > G variants known as causal for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 5-12%, lower than in mitochondrial diseases. Despite the limitation of using peripheral tissues, our DES investigation supports the possible contribution of deleterious mosaic variants in the nuclear genome responsible for severer phenotypes, such as DD/ASD, to the risk of BD and further demonstrates that the same paradigm can be applied to the mitochondrial genome. These results, as well as the enrichment of heteroplasmic mitochondrial tRNA variants in BD, add a new piece to the understanding of the genetic architecture of BD and provide general insights into the pathological roles of mosaic variants in human diseases.

  35. Comprehensive evaluation of machine learning algorithms for predicting sleep-wake conditions and differentiating between the wake conditions before and after sleep during pregnancy based on heart rate variability. International-journal Peer-reviewed

    Xue Li, Chiaki Ono, Noriko Warita, Tomoka Shoji, Takashi Nakagawa, Hitomi Usukura, Zhiqian Yu, Yuta Takahashi, Kei Ichiji, Norihiro Sugita, Natsuko Kobayashi, Saya Kikuchi, Ryoko Kimura, Yumiko Hamaie, Mizuki Hino, Yasuto Kunii, Keiko Murakami, Mami Ishikuro, Taku Obara, Tomohiro Nakamura, Fuji Nagami, Takako Takai, Soichi Ogishima, Junichi Sugawara, Tetsuro Hoshiai, Masatoshi Saito, Gen Tamiya, Nobuo Fuse, Susumu Fujii, Masaharu Nakayama, Shinichi Kuriyama, Masayuki Yamamoto, Nobuo Yaegashi, Noriyasu Homma, Hiroaki Tomita

    Frontiers in psychiatry　14　1104222-1104222　2023

    DOI： 10.3389/fpsyt.2023.1104222 　

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    INTRODUCTION: Perinatal women tend to have difficulties with sleep along with autonomic characteristics. This study aimed to identify a machine learning algorithm capable of achieving high accuracy in predicting sleep-wake conditions and differentiating between the wake conditions before and after sleep during pregnancy based on heart rate variability (HRV). METHODS: Nine HRV indicators (features) and sleep-wake conditions of 154 pregnant women were measured for 1 week, from the 23rd to the 32nd weeks of pregnancy. Ten machine learning and three deep learning methods were applied to predict three types of sleep-wake conditions (wake, shallow sleep, and deep sleep). In addition, the prediction of four conditions, in which the wake conditions before and after sleep were differentiated-shallow sleep, deep sleep, and the two types of wake conditions-was also tested. RESULTS AND DISCUSSION: In the test for predicting three types of sleep-wake conditions, most of the algorithms, except for Naïve Bayes, showed higher areas under the curve (AUCs; 0.82-0.88) and accuracy (0.78-0.81). The test using four types of sleep-wake conditions with differentiation between the wake conditions before and after sleep also resulted in successful prediction by the gated recurrent unit with the highest AUC (0.86) and accuracy (0.79). Among the nine features, seven made major contributions to predicting sleep-wake conditions. Among the seven features, "the number of interval differences of successive RR intervals greater than 50 ms (NN50)" and "the proportion dividing NN50 by the total number of RR intervals (pNN50)" were useful to predict sleep-wake conditions unique to pregnancy. These findings suggest alterations in the vagal tone system specific to pregnancy.

  36. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. International-journal Peer-reviewed

    Stavroula Kanoni, Sarah E Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W Winkler, Adam E Locke, Eirini Marouli, Greg J M Zajac, Kuan-Han H Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M Brumpton, Humaira Rasheed, Aki S Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J Kullo, Akira Narita, Jun Takayama, Hilary C Martin, Karen A Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E Miller, Archie Campbell, Kuang Lin, Iona Y Millwood, Asif Rasheed, George Hindy, Jessica D Faul, Wei Zhao, David R Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R Brown, Weihua Zhang, Ketian Yu, Ellen M Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian'an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A Yousri, Ruth E Mitchell, Jin Fang Chai, Mette Aadahl, Anne A Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R Warren, Julia Ramirez, Jette Bork-Jensen, Line L Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E Galesloot, Jonathan P Bradfield, Sanni E Ruotsalainen, EWarwick Daw, Joseph M Zmuda, Jonathan S Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A Brody, Miguel Vazquez-Moreno, Mary F Feitosa, Mary K Wojczynski, Zhe Wang, Michael H Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W Benjamins, Jorgen Engmann, Noah L Tsao, Anurag Verma, Roderick C Slieker, Ken Sin Lo, Nuno R Zilhao, Phuong Le, Marcus E Kleber, Graciela E Delgado, Shaofeng Huo, Daisuke D Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S Nongmaithem, Swati Bayyana, Heather M Stringham, Marguerite R Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R H J Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C Warner, Ya Xing Wang, Wen B Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F Bielak, Jennifer A Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J van der Most, Niina Pitkänen, Brian E Cade, Sander W van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R Bentley, Ayo P Doumatey, Adebowale A Adeyemo, Jong Young Lee, Eva R B Petersen, Aneta A Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W Rayner, Carol A Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D Jackson, Alexander P Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C Bis, Lenore J Launer, Huaixing Li, Mike A Nalls, Olli T Raitakari, Sahoko Ichihara, Sarah H Wild, Christopher P Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J de Borst, Eung Kweon Kim, Hieab H H Adams, M Arfan Ikram, Xiaofeng Zhu, Folkert W Asselbergs, Adriaan O Kraaijeveld, Joline W J Beulens, Xiao-Ou Shu, Loukianos S Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E Pennell, Trevor A Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M Heid, Klaus J Stark, Martina E Zimmermann, Henry Völzke, Georg Homuth, Michele K Evans, Alan B Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E Hoefer, Susan Redline, Katja Pahkala, Albertine J Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L R Kardia, Patricia A Peyser, Norihiro Kato, Matthias B Schulze, Giorgia Girotto, Carsten A Böger, Bettina Jung, Peter K Joshi, David A Bennett, Philip L De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J Caulfield, Patricia B Munroe, Xiuqing Guo, Marina Ciullo, Jost B Jonas, Nilesh J Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Linda S Adair, Sonny Augustin Bechayda, H Janaka de Silva, Ananda R Wickremasinghe, Ronald M Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G Wilson, Lars Lind, Chew-Kiat Heng, Amanda E Nelson, Yvonne M Golightly, James F Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J Scott, D C Rao, Donna K Arnett, Steven C Hunt, Mark Walker, Heikki A Koistinen, Giriraj R Chandak, Josep M Mercader, Maria C Costanzo, Dongkeun Jang, Noël P Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I McCarthy, Colin N A Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M 't Hart, Petra J M Elders, Scott M Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D Spector, Ruth J F Loos, Michael A Province, Esteban J Parra, Miguel Cruz, Bruce M Psaty, Ivan Brandslund, Peter P Pramstaller, Charles N Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F A Grant, Lambertus A L M Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W Franks, Allan Linneberg, J Wouter Jukema, Amit V Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I Rotter, Thomas M Dantoft, Fredrik Karpe, Matt J Neville, Nicholas J Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T Hattersley, Nancy L Pedersen, Patrik K E Magnusson, Dorret I Boomsma, Allegonda H M Willemsen, LAdrienne Cupples, Joyce B J van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C Chambers, Jaspal S Kooner, Paul S de Vries, Alanna C Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E North, Martha Daviglus, Peter Kraft, Nicholas G Martin, John B Whitfield, Shahid Abbas, Danish Saleheen, Robin G Walters, Michael V Holmes, Corri Black, Blair H Smith, Aris Baras, Anne E Justice, Julie E Buring, Paul M Ridker, Daniel I Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A van Heel, Richard C Trembath, Wei-Qi Wei, Gail P Jarvik, Bahram Namjou, M Geoffrey Hayes, Marylyn D Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A Lynch, Daniel J Rader, Philip S Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, John M Gaziano, Peter W F Wilson, Timothy M Frayling, Joel N Hirschhorn, Sekar Kathiresan, Karen L Mohlke, Yan V Sun, Andrew P Morris, Michael Boehnke, Christopher D Brown, Pradeep Natarajan, Panos Deloukas, Cristen J Willer, Themistocles L Assimes, Gina M Peloso

    Genome biology　23　(1)　268-268　2022/12/27

    DOI： 10.1186/s13059-022-02837-1 　

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    BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

  37. Familial Paget’s disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27) Peer-reviewed

    Akiko Saito-Hakoda, Atsuo Kikuchi, Tadahisa Takahashi, Yu Yokoyama, Noriko Himori, Mika Adachi, Ryoukichi Ikeda, Yuri Nomura, Jun Takayama, Junko Kawashima, Fumiki Katsuoka, Fumiyoshi Fujishima, Takehiko Yamaguchi, Akiyo Ito, Takushi Hanita, Junko Kanno, Toshimi Aizawa, Toru Nakazawa, Tetsuaki Kawase, Gen Tamiya, Masayuki Yamamoto, Ikuma Fujiwara, Shigeo Kure

    Journal of Bone and Mineral Metabolism　41　(2)　193-202　2022/12/15

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1007/s00774-022-01392-w 　

    ISSN： 0914-8779

    eISSN： 1435-5604

  38. Genome-wide association study of the risk of chronic kidney disease and kidney-related traits in the Japanese population: J-Kidney-Biobank. International-journal Peer-reviewed

    Yuka Sugawara, Yosuke Hirakawa, Hajime Nagasu, Akira Narita, Akihiro Katayama, Jun Wada, Miho Shimizu, Takashi Wada, Hiromasa Kitamura, Toshiaki Nakano, Hideki Yokoi, Motoko Yanagita, Shin Goto, Ichiei Narita, Seizo Koshiba, Gen Tamiya, Masaomi Nangaku, Masayuki Yamamoto, Naoki Kashihara

    Journal of human genetics　2022/11/21

    DOI： 10.1038/s10038-022-01094-1 　

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    Chronic kidney disease (CKD) is a syndrome characterized by a gradual loss of kidney function with decreased estimated glomerular filtration rate (eGFR), which may be accompanied by an increase in the urine albumin-to-creatinine ratio (UACR). Although trans-ethnic genome-wide association studies (GWASs) have been conducted for kidney-related traits, there have been few analyses in the Japanese population, especially for the UACR trait. In this study, we conducted a GWAS to identify loci related to multiple kidney-related traits in Japanese individuals. First, to detect loci associated with CKD, eGFR, and UACR, we performed separate GWASs with the following two datasets: 475 cases of CKD diagnosed at seven university hospitals and 3471 healthy subjects (dataset 1) and 3664 cases of CKD-suspected individuals with eGFR <60 ml/min/1.73 m2 or urinary protein ≥ 1+ and 5952 healthy subjects (dataset 2). Second, we performed a meta-analysis between these two datasets and detected the following associated loci: 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among the loci detected, 22 have never been reported previously. Half of the significant loci for CKD were shared with those for eGFR, whereas most of the loci associated with UACR were different from those associated with CKD or eGFR. The GWAS of the Japanese population identified novel genetic components that were not previously detected. The results also suggest that the group primarily characterized by increased UACR possessed genetically different features from the group characterized by decreased eGFR.

  39. Pathological variants in genes associated with disorders of sex development and central causes of hypogonadism in a whole-genome reference panel of 8380 Japanese individuals. International-journal Peer-reviewed

    Naomi Shiga, Yumi Yamaguchi-Kabata, Saori Igeta, Jun Yasuda, Shu Tadaka, Takamichi Minato, Zen Watanabe, Junko Kanno, Gen Tamiya, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Akiko Kondo, Masahito Tachibana, Masayuki Yamamoto, Nobuo Yaegashi, Junichi Sugawara

    Human genome variation　9　(1)　34-34　2022/09/28

    DOI： 10.1038/s41439-022-00213-w 　

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    Disorders of sex development (DSD) comprises a congenital condition in which chromosomal, gonadal, or anatomical sex development is atypical. In this study, we screened for pathogenic variants in 32 genes associated with DSDs and central causes of hypogonadism (CHG) in a whole-genome reference panel including 8380 Japanese individuals constructed by Tohoku Medical Megabank Organization. Candidate pathogenic (P) or likely pathogenic (LP) variants were extracted from the ClinVar, InterVar, and Human Gene Mutation databases. Ninety-one candidate pathological variants were found in 25 genes; 28 novel candidate variants were identified. Nearly 1 in 40 (either ClinVar or InterVar P or LP) to 157 (both ClinVar and InterVar P or LP) individuals were found to be carriers of recessive DSD and CHG alleles. In these data, genes implicated in gonadal dysfunction did not show loss-of-function variants, with a relatively high tendency of intolerance for haploinsufficiency based on pLI and Episcore, both of which can be used for estimating haploinsufficiency. We report the types and frequencies of causative variants for DSD and CHG in the general Japanese population. This study furthers our understanding of the genetic causes and helps to refine genetic counseling of DSD and CHG.

  40. Construction of a trio-based structural variation panel utilizing activated T lymphocytes and long-read sequencing technology. International-journal Peer-reviewed

    Akihito Otsuki, Yasunobu Okamura, Noriko Ishida, Shu Tadaka, Jun Takayama, Kazuki Kumada, Junko Kawashima, Keiko Taguchi, Naoko Minegishi, Shinichi Kuriyama, Gen Tamiya, Kengo Kinoshita, Fumiki Katsuoka, Masayuki Yamamoto

    Communications biology　5　(1)　991-991　2022/09/20

    DOI： 10.1038/s42003-022-03953-1 　

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    Long-read sequencing technology enable better characterization of structural variants (SVs). To adapt the technology to population-scale analyses, one critical issue is to obtain sufficient amount of high-molecular-weight genomic DNA. Here, we propose utilizing activated T lymphocytes, which can be established efficiently in a biobank to stably supply high-grade genomic DNA sufficiently. We conducted nanopore sequencing of 333 individuals constituting 111 trios with high-coverage long-read sequencing data (depth 22.2x, N50 of 25.8 kb) and identified 74,201 SVs. Our trio-based analysis revealed that more than 95% of the SVs were concordant with Mendelian inheritance. We also identified SVs associated with clinical phenotypes, all of which appear to be stably transmitted from parents to offspring. Our data provide a catalog of SVs in the general Japanese population, and the applied approach using the activated T-lymphocyte resource will contribute to biobank-based human genetic studies focusing on SVs at the population scale.

  41. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids Peer-reviewed

    Shweta Ramdas, Jonathan Judd, Sarah E. Graham, Stavroula Kanoni, Yuxuan Wang, Ida Surakka, Brandon Wenz, Shoa L. Clarke, Alessandra Chesi, Andrew Wells, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J.M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Wen-Jane Lee, Chao Agnes Hsiung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Sebastian Schönherr, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, E. Warwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Phuong Le, Mary F. Feitosa, Mary K. Wojczynski, Daiane Hemerich, Michael Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Tsao L. Noah, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Carina Emmel, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Alagu Sankareswaran, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R.H.J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Anna Morgan, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R.B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Karen Y. He, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H.H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W.J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke I. den Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D.C. Rao, Donna K. Arnett, Mark Walker, Laura J. Scott, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, E. Shyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N.A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Fan Lu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M. t Hart, Petra J.M. Elders, Daniel J. Rader, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J.F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F.A. Grant, Lambertus Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Wayne Huey-Herng Sheu, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K.E. Magnusson, Dorret I. Boomsma, Eco J.C. de Geus, L. Adrienne Cupples, Joyce B.J. van Meurs, Arfan Ikram, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Jaakko Tuomilehto, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, Y. Eugene Chen, Yuk-Lam Ho, Julie A. Lynch, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O'Donnell, John M. Gaziano, Peter Wilson, Karen L. Mohlke, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Michael Boehnke, Struan Grant, Pradeep Natarajan, Yan V. Sun, Andrew P. Morris, Panos Deloukas, Gina Peloso, Themistocles L. Assimes, Cristen J. Willer, Xiang Zhu, Christopher D. Brown

    The American Journal of Human Genetics　109　(8)　1366-1387　2022/08

    Publisher: Elsevier BV

    DOI： 10.1016/j.ajhg.2022.06.012 　

    ISSN： 0002-9297

  42. Two Siblings with Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome 4 and a Novel Variant of ATP8A2. Peer-reviewed

    Yuta Narishige, Hisao Yaoita, Moriei Shibuya, Miki Ikeda, Kaori Kodama, Aritomo Kawashima, Yukimune Okubo, Wakaba Endo, Takehiko Inui, Noriko Togashi, Soichiro Tanaka, Yasuko Kobayashi, Akira Onuma, Jun Takayama, Gen Tamiya, Atsuo Kikuchi, Shigeo Kure, Kazuhiro Haginoya

    The Tohoku journal of experimental medicine　256　(4)　321-326　2022/04/29

    DOI： 10.1620/tjem.2022.J010 　

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    Cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) is early onset neuromotor disorder and intellectual disabilities caused by variants of ATP8A2. We report sibling cases and systematically analyze previous literature to increase our understanding of CAMRQ4. Japanese siblings presented with athetotic movements at 1 and 2 months of age. They also had ptosis, ophthalmoplegia, feeding difficulty, hypotonia, and severely delayed development. One patient had retinal degeneration and optic atrophy. Flattening of the auditory brainstem responses and areflexia developed. At the last follow-up, neither patient could sit or achieve head control, although some nonverbal communication was preserved. Whole exome sequencing revealed compound heterozygous variants of ATP8A2: NM_016529.6:c.[1741C>T];[2158C>T] p.[(Arg581*)];[(Arg720*)]. The p.(Arg581*) variant has been reported, while the variant p.(Arg720*) was novel. The symptoms did not progress in the early period of development, which makes it difficult to distinguish from dyskinetic cerebral palsy, particularly in solitary cases. However, visual and hearing impairments associated with involuntary movements and severe developmental delay may be a clue to suspect CAMRQ4.

  43. The longest reported sibling survivors of a severe form of congenital myasthenic syndrome with the ALG14 pathogenic variant. International-journal Peer-reviewed

    Yu Katata, Saki Uneoka, Naoya Saijyo, Yu Aihara, Takamitsu Miyazoe, Shun Koyamaishi, Yoshitsugu Oikawa, Yuya Ito, Yu Abe, Yurika Numata-Uematsu, Jun Takayama, Atsuo Kikuchi, Gen Tamiya, Mitsugu Uematsu, Shigeo Kure

    American journal of medical genetics. Part A　188　(4)　1293-1298　2022/04

    DOI： 10.1002/ajmg.a.62629 　

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    Congenital myasthenic syndromes (CMS) is a group of diseases that causes abnormalities at the neuromuscular junction owing to genetic anomalies. The pathogenic variant in ALG14 results in a severe pathological form of CMS causing end-plate acetylcholine receptor deficiency. Here, we report the cases of two siblings with CMS associated with a novel variant in ALG14. Immediately after birth, they showed hypotonia and multiple joint contractures with low Apgar scores. Ptosis, low-set ears, and high-arched palate were noted. Deep tendon reflexes were symmetrical. They showed worsening swallowing and respiratory problems; hence, nasal feeding and tracheotomy were performed. Cranial magnetic resonance imaging scans revealed delayed myelination and cerebral atrophy. Exome sequencing indicated that the siblings had novel compound heterozygous missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon 4 of ALG14. Repetitive nerve stimulation test showed an abnormal decrease in compound muscle action potential. After treatment with pyridostigmine, the time off the respirator increased. Their epileptic seizures were well controlled by anti-epileptic drugs. Their clinical course is stable even now at the ages of 5 and 2 years, making them the longest reported survivors of a severe form of CMS with the ALG14 variant thus far.

  44. Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct. International-journal Peer-reviewed

    Miyako Kanno, Mitsuyoshi Suzuki, Ken Tanikawa, Chikahiko Numakura, Shu-Ichi Matsuzawa, Tetsuya Niihori, Yoko Aoki, Yoichi Matsubara, Satoshi Makino, Gen Tamiya, Satoshi Nakano, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Tetsuo Mitsui, Kiyoshi Hayasaka

    Journal of human genetics　2022/01/28

    DOI： 10.1038/s10038-022-01017-0 　

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    Paucity of interlobular bile ducts (PILBD) is a heterogeneous disorder classified into two categories, syndromic and non-syndromic bile duct paucity. Syndromic PILBD is characterized by the presence of clinical manifestations of Alagille syndrome. Non-syndromic PILBD is caused by multiple diseases, such as metabolic and genetic disorders, infectious diseases, and inflammatory and immune disorders. We evaluated a family with a dominantly inherited PILBD, who presented with cholestasis at 1-2 months of age but spontaneously improved by 1 year of age. Next-generation sequencing analysis revealed a heterozygous CACYBP/SIP p.E177Q pathogenic variant. Calcyclin-binding protein and Siah1 interacting protein (CACYBP/SIP) form a ubiquitin ligase complex and induce proteasomal degradation of non-phosphorylated β-catenin. Immunohistochemical analysis revealed a slight decrease in CACYBP and β-catenin levels in the liver of patients in early infancy, which almost normalized by 13 months of age. The CACYBP/SIP p.E177Q pathogenic variant may form a more active or stable ubiquitin ligase complex that enhances the degradation of β-catenin and delays the maturation of intrahepatic bile ducts. Our findings indicate that accurate regulation of the β-catenin concentration is essential for the development of intrahepatic bile ducts and CACYBP/SIP pathogenic variant is a novel cause of PILDB.

  45. Development of a prognostic prediction support system for cervical intraepithelial neoplasia using artificial intelligence-based diagnosis Peer-reviewed

    Takayuki Takahashi, Hikaru Matsuoka, Rieko Sakurai, Jun Akatsuka, Yusuke Kobayashi, Masaru Nakamura, Takashi Iwata, Kouji Banno, Motomichi Matsuzaki, Jun Takayama, Daisuke Aoki, Yoichiro Yamamoto, Gen Tamiya

    Journal of Gynecologic Oncology　2022

    DOI： 10.3802/jgo.2022.33.e57 　

  46. The power of genetic diversity in genome-wide association studies of lipids Peer-reviewed

    Sarah E. Graham, Shoa L. Clarke, Kuan-Han H. Wu, Stavroula Kanoni, Greg J. M. Zajac, Shweta Ramdas, Ida Surakka, Ioanna Ntalla, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Mi Yeong Hwang, Sohee Han, Akira Narita, Ananyo Choudhury, Amy R. Bentley, Kenneth Ekoru, Anurag Verma, Bhavi Trivedi et al. (Gen Tamiya 513th in 530 authors)

    Nature　600　(7890)　675-679　2021/12/23

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41586-021-04064-3 　

    ISSN： 0028-0836

    eISSN： 1476-4687

  47. dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project Peer-reviewed

    Soichi Ogishima, Satoshi Nagaie, Satoshi Mizuno, Ryosuke Ishiwata, Keita Iida, Kazuro Shimokawa, Takako Takai-Igarashi, Naoki Nakamura, Sachiko Nagase, Tomohiro Nakamura, Naho Tsuchiya, Naoki Nakaya, Keiko Murakami, Fumihiko Ueno, Tomomi Onuma, Mami Ishikuro, Taku Obara, Shunji Mugikura, Hiroaki Tomita, Akira Uruno et al. (Gen Tamiya 28th in 52 authors)

    Human Genome Variation　8　44　2021/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41439-021-00175-5 　

    eISSN： 2054-345X

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    <title>Abstract</title>To reveal gene-environment interactions underlying common diseases and estimate the risk for common diseases, the Tohoku Medical Megabank (TMM) project has conducted prospective cohort studies and genomic and multiomics analyses. To establish an integrated biobank, we developed an integrated database called “dbTMM” that incorporates both the individual cohort/clinical data and the genome/multiomics data of 157,191 participants in the Tohoku Medical Megabank project. To our knowledge, dbTMM is the first database to store individual whole-genome data on a variant-by-variant basis as well as cohort/clinical data for over one hundred thousand participants in a prospective cohort study. dbTMM enables us to stratify our cohort by both genome-wide genetic factors and environmental factors, and it provides a research and development platform that enables prospective analysis of large-scale data from genome cohorts.

  48. A cross-population atlas of genetic associations for 220 human phenotypes Peer-reviewed

    Saori Sakaue, Masahiro Kanai, Yosuke Tanigawa, Juha Karjalainen, Mitja Kurki, Seizo Koshiba, Akira Narita, Takahiro Konuma, Kenichi Yamamoto, Masato Akiyama, Kazuyoshi Ishigaki, Akari Suzuki, Ken Suzuki, Wataru Obara, Ken Yamaji, Kazuhisa Takahashi, Satoshi Asai, Yasuo Takahashi, Takao Suzuki, Nobuaki Shinozaki, Hiroki Yamaguchi, Shiro Minami, Shigeo Murayama, Kozo Yoshimori, Satoshi Nagayama, Daisuke Obata, Masahiko Higashiyama, Akihide Masumoto, Yukihiro Koretsune, Kaoru Ito, Chikashi Terao, Toshimasa Yamauchi, Issei Komuro, Takashi Kadowaki, Gen Tamiya, Masayuki Yamamoto, Yusuke Nakamura, Michiaki Kubo, Yoshinori Murakami, Kazuhiko Yamamoto, Yoichiro Kamatani, Aarno Palotie, Manuel A. Rivas, Mark J. Daly, Koichi Matsuda, Yukinori Okada

    Nature Genetics　53　(10)　1415-1424　2021/10

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41588-021-00931-x 　

    ISSN： 1061-4036

    eISSN： 1546-1718

  49. Smooth-threshold multivariate genetic prediction incorporating gene–environment interactions Peer-reviewed

    Masao Ueki, Gen Tamiya

    G3 Genes|Genomes|Genetics　2021/08/06

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/g3journal/jkab278 　

    eISSN： 2160-1836

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    <title>Abstract</title> We propose a genetic prediction modeling approach for genome-wide association study (GWAS) data that can include not only marginal gene effects but also gene-environment (GxE) interaction effects—i.e., multiplicative effects of environmental factors with genes rather than merely additive effects of each. The proposed approach is a straightforward extension of our previous multiple-regression-based method, STMGP (smooth-threshold multivariate genetic prediction), with the new feature being that genome-wide test statistics from a GxE interaction analysis are used to weight the corresponding variants. We develop a simple univariate regression approximation to the GxE interaction effect that allows a direct fit of the STMGP framework without modification. The sparse nature of our model automatically removes irrelevant predictors (including variants and GxE combinations), and the model is able to simultaneously incorporate multiple environmental variables. Simulation studies to evaluate the proposed method in comparison with other modeling approaches demonstrate its superior performance under the presence of GxE interaction effects. We illustrate the usefulness of our prediction model through application to real GWAS data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

  50. A patient with early-onset SMAX3 and a novel variant of ATP7A Peer-reviewed

    Moriei Shibuya, Hisao Yaoita, Kaori Kodama, Yukimune Okubo, Wakaba Endo, Takehiko Inui, Noriko Togashi, Jun Takayama, Gen Tamiya, Atsuo Kikuchi, Shigeo Kure, Kazuhiro Haginoya

    Brain and Development　2021/08

    Publisher: Elsevier BV

    DOI： 10.1016/j.braindev.2021.08.004 　

    ISSN： 0387-7604

  51. Identification and Validation of Combination Plasma Biomarker of Afamin, Fibronectin and Sex Hormone-Binding Globulin to Predict Pre-eclampsia Peer-reviewed

    Yasuo Uchida, Tomoya Higuchi, Matsuyuki Shirota, Satoshi Kagami, Daisuke Saigusa, Seizo Koshiba, Jun Yasuda, Gen Tamiya, Shinichi Kuriyama, Kengo Kinoshita, Nobuo Yaegashi, Masayuki Yamamoto, Tetsuya Terasaki, Junichi Sugawara

    Biological and Pharmaceutical Bulletin　44　(6)　804-815　2021/06/01

    Publisher: Pharmaceutical Society of Japan

    DOI： 10.1248/bpb.b20-01043 　

    ISSN： 0918-6158

    eISSN： 1347-5215

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    The purpose of the present study was to identify a plasma protein biomarker able to predict pre-eclampsia (PE). Comprehensive quantitative proteomics using mass spectrometry with sequential window acquisition of all theoretical fragment ion spectra (SWATH-MS) was applied to plasma samples of 7 PE and 14 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE), and 11 proteins were selected as candidates potentially able to differentiate the two groups. Plasmas collected at gestational weeks 14-24 from 36 PE and 120 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE) were used to conduct selected reaction monitoring quantification analysis, optimize protein combinations and conduct internal validation, which consisted of 30 iterations of 10-fold cross-validation using multivariate logistic regression and receiver operating characteristic (ROC) analysis. The combination of afamin, fibronectin, and sex-hormone-binding globulin was selected as the best candidate. The 3-protein combination predictive model (predictive equation and cut-off value) generated using the internal validation subjects was successfully validated in another group of validation subjects (36 PE and 54 healthy (for PE subjects, plasma samples were taken before onset of PE)) and showed good predictive performance, with the area under the curve (AUC) 0.835 and odds ratio 13.43. In conclusion, we newly identified a 3-protein combination biomarker and established a predictive equation and cut-off value that can predict the onset of PE based on analysis of plasma samples collected during gestational weeks 14-24.

  52. Japonica Array NEO with increased genome-wide coverage and abundant disease risk SNPs Peer-reviewed

    Mika Sakurai-Yageta, Kazuki Kumada, Chinatsu Gocho, Satoshi Makino, Akira Uruno, Shu Tadaka, Ikuko N Motoike, Masae Kimura, Shin Ito, Akihito Otsuki, Akira Narita, Hisaaki Kudo, Yuichi Aoki, Inaho Danjoh, Jun Yasuda, Hiroshi Kawame, Naoko Minegishi, Seizo Koshiba, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

    The Journal of Biochemistry　2021/05/13

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/jb/mvab060 　

    ISSN： 0021-924X

    eISSN： 1756-2651

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    <title>Abstract</title> Ethnic-specific SNP arrays are becoming more important to increase the power of genome-wide association studies in diverse population. In the Tohoku Medical Megabank Project, we have been developing a series of Japonica Arrays (JPA) for genotyping participants based on reference panels constructed from whole-genome sequence data of the Japanese population. Here, we designed a novel version of the SNP array for the Japanese population, called Japonica Array NEO (JPA NEO), comprising a total of 666,883 markers. Among them, 654,246 tag SNPs of autosomes and X chromosome were selected from an expanded reference panel of 3,552 Japanese, 3.5KJPNv2, using pairwise r2 of linkage disequilibrium measures. Additionally, 28,298 markers were included for the evaluation of previously identified disease risk markers from the literature and databases, and those present in the Japanese population were extracted using the reference panel. Through genotyping 286 Japanese samples, we found that the imputation quality r2 and INFO score in the minor allele frequency bin &amp;gt;2.5–5% were &amp;gt;0.9 and &amp;gt;0.8, respectively, and &amp;gt;12 million markers were imputed with an INFO score &amp;gt;0.8. From these results, JPA NEO is a promising tool for genotyping the Japanese population with genome-wide coverage, contributing to the development of genetic risk scores.

  53. GWAS Identified IL4R and the Major Histocompatibility Complex Region as the Associated Loci of Total Serum IgE Levels in 9,260 Japanese Individuals Peer-reviewed

    Kosuke Shido, Kaname Kojima, Matsuyuki Shirota, Kenshi Yamasaki, Ikuko N. Motoike, Atsushi Hozawa, Soichi Ogishima, Naoko Minegishi, Kozo Tanno, Fumiki Katsuoka, Gen Tamiya, Setsuya Aiba, Masayuki Yamamoto, Kengo Kinoshita

    Journal of Investigative Dermatology　2021/04

    Publisher: Elsevier BV

    DOI： 10.1016/j.jid.2021.02.762 　

    ISSN： 0022-202X

  54. Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk International-journal Peer-reviewed

    Daichi Shigemizu, Risa Mitsumori, Shintaro Akiyama, Akinori Miyashita, Takashi Morizono, Sayuri Higaki, Yuya Asanomi, Norikazu Hara, Gen Tamiya, Kengo Kinoshita, Takeshi Ikeuchi, Shumpei Niida, Kouichi Ozaki

    Translational Psychiatry　11　(1)　151-151　2021/03

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41398-021-01272-3 　

    eISSN： 2158-3188

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    <title>Abstract</title>Alzheimer’s disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including <italic>APOE</italic> and <italic>SORL1</italic>, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case–control cohort. The novel locus <italic>FAM47E</italic> reached genome-wide significance in a meta-analysis of association results. This is the first report associating the <italic>FAM47E</italic> locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer’s Project identified an additional novel susceptibility locus in <italic>OR2B2</italic>. Our data highlight the importance of performing GWAS in non-European populations.

  55. Body mass index and colorectal cancer risk: A Mendelian randomization study International-journal Peer-reviewed

    Shiori Suzuki, Atsushi Goto, Masahiro Nakatochi, Akira Narita, Taiki Yamaji, Norie Sawada, Ryoko Katagiri, Masao Iwagami, Akiko Hanyuda, Tsuyoshi Hachiya, Yoichi Sutoh, Isao Oze, Yuriko N. Koyanagi, Yumiko Kasugai, Yukari Taniyama, Hidemi Ito, Hiroaki Ikezaki, Yuichiro Nishida, Takashi Tamura, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Etsuko Ozaki, Kiyonori Kuriki, Naoyuki Takashima, Kokichi Arisawa, Kenji Takeuchi, Kozo Tanno, Atsushi Shimizu, Gen Tamiya, Atsushi Hozawa, Kengo Kinoshita, Kenji Wakai, Makoto Sasaki, Masayuki Yamamoto, Keitaro Matsuo, Shoichiro Tsugane, Motoki Iwasaki

    Cancer Science　112　(4)　1579-1588　2021/02/25

    Publisher: Wiley

    DOI： 10.1111/cas.14824 　

    ISSN： 1347-9032

    eISSN： 1349-7006

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    Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two-sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome-wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP-BMI associations, we undertook a meta-analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J-CGE), comprising normal populations. For the analysis of SNP-CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta-analysis. Mendelian randomization analysis of inverse-variance weighted method indicated that a one-unit (kg/m2 ) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06-1.20; P value <.001) for CRC using the set of 68 SNPs, and an odds ratio of 1.07 (1.03-1.11, 0.001) for CRC using the set of 654 SNPs. Sensitivity analyses robustly showed increased odds ratios for CRC for every one-unit increase in genetically predicted BMI. Our MR analyses strongly support the evidence that higher BMI influences the risk of CRC. Although Asians are generally leaner than Europeans and North Americans, avoiding higher BMI seems to be important for the prevention of CRC in Asian populations.

  56. ALOX12 mutation in a family with dominantly inherited bleeding diathesis Peer-reviewed

    Tetsuo Mitsui, Satoshi Makino, Gen Tamiya, Hiroko Sato, Yuki Kawakami, Yoshitaka Takahashi, Toru Meguro, Hiroko Izumino, Yosuke Sudo, Ikuo Norota, Kuniaki Ishii, Kiyoshi Hayasaka

    Journal of Human Genetics　2021/02/10

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s10038-020-00887-6 　

    ISSN： 1434-5161

    eISSN： 1435-232X

  57. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries Peer-reviewed

    Puya Gharahkhani, Eric Jorgenson, Pirro Hysi, Anthony P. Khawaja, Sarah Pendergrass, Xikun Han, Jue Sheng Ong, Alex W. Hewitt, Ayellet V. Segrè, John M. Rouhana, Andrew R. Hamel, Robert P. Igo, Helene Choquet, Ayub Qassim, Navya S. Josyula, Jessica N. Cooke Bailey, Pieter W. M. Bonnemaijer, Adriana Iglesias, Owen M. Siggs, Terri L. Young, Veronique Vitart, Alberta A. H. J. Thiadens, Juha Karjalainen, Steffen Uebe, Ronald B. Melles, K. Saidas Nair, Robert Luben, Mark Simcoe, Nishani Amersinghe, Angela J. Cree, Rene Hohn, Alicia Poplawski, Li Jia Chen, Shi-Song Rong, Tin Aung, Eranga Nishanthie Vithana, Gen Tamiya, Yukihiro Shiga, Masayuki Yamamoto, Toru Nakazawa, Hannah Currant, Ewan Birney, Xin Wang, Adam Auton, Michelle K. Lupton, Nicholas G. Martin, Adeyinka Ashaye, Olusola Olawoye, Susan E. Williams, Stephen Akafo, Michele Ramsay, Kazuki Hashimoto, Yoichiro Kamatani, Masato Akiyama, Yukihide Momozawa, Paul J. Foster, Peng T. Khaw, James E. Morgan, Nicholas G. Strouthidis, Peter Kraft, Jae H. Kang, Chi Pui Pang, Francesca Pasutto, Paul Mitchell, Andrew J. Lotery, Aarno Palotie, Cornelia van Duijn, Jonathan L. Haines, Chris Hammond, Louis R. Pasquale, Caroline C. W. Klaver, Michael Hauser, Chiea Chuen Khor, David A. Mackey, Michiaki Kubo, Ching-Yu Cheng, Jamie E. Craig, Stuart MacGregor, Janey L. Wiggs

    Nature Communications　12　(1)　1258　2021/02

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41467-020-20851-4 　

    eISSN： 2041-1723

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    <title>Abstract</title>Primary open-angle glaucoma (POAG), is a heritable common cause of blindness world-wide. To identify risk loci, we conduct a large multi-ethnic meta-analysis of genome-wide association studies on a total of 34,179 cases and 349,321 controls, identifying 44 previously unreported risk loci and confirming 83 loci that were previously known. The majority of loci have broadly consistent effects across European, Asian and African ancestries. Cross-ancestry data improve fine-mapping of causal variants for several loci. Integration of multiple lines of genetic evidence support the functional relevance of the identified POAG risk loci and highlight potential contributions of several genes to POAG pathogenesis, including <italic>SVEP1, RERE, VCAM1, ZNF638</italic>, <italic>CLIC5, SLC2A12, YAP1, MXRA5</italic>, and <italic>SMAD6</italic>. Several drug compounds targeting POAG risk genes may be potential glaucoma therapeutic candidates.

  58. Heart Rate Information-Based Machine Learning Prediction of Emotions Among Pregnant Women. International-journal Peer-reviewed

    Xue Li, Chiaki Ono, Noriko Warita, Tomoka Shoji, Takashi Nakagawa, Hitomi Usukura, Zhiqian Yu, Yuta Takahashi, Kei Ichiji, Norihiro Sugita, Natsuko Kobayashi, Saya Kikuchi, Yasuto Kunii, Keiko Murakami, Mami Ishikuro, Taku Obara, Tomohiro Nakamura, Fuji Nagami, Takako Takai, Soichi Ogishima, Junichi Sugawara, Tetsuro Hoshiai, Masatoshi Saito, Gen Tamiya, Nobuo Fuse, Shinichi Kuriyama, Masayuki Yamamoto, Nobuo Yaegashi, Noriyasu Homma, Hiroaki Tomita

    Frontiers in psychiatry　12　799029-799029　2021

    DOI： 10.3389/fpsyt.2021.799029 　

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    In this study, the extent to which different emotions of pregnant women can be predicted based on heart rate-relevant information as indicators of autonomic nervous system functioning was explored using various machine learning algorithms. Nine heart rate-relevant autonomic system indicators, including the coefficient of variation R-R interval (CVRR), standard deviation of all NN intervals (SDNN), and square root of the mean squared differences of successive NN intervals (RMSSD), were measured using a heart rate monitor (MyBeat) and four different emotions including "happy," as a positive emotion and "anxiety," "sad," "frustrated," as negative emotions were self-recorded on a smartphone application, during 1 week starting from 23rd to 32nd weeks of pregnancy from 85 pregnant women. The k-nearest neighbor (k-NN), support vector machine (SVM), logistic regression (LR), random forest (RF), naïve bayes (NB), decision tree (DT), gradient boosting trees (GBT), stochastic gradient descent (SGD), extreme gradient boosting (XGBoost), and artificial neural network (ANN) machine learning methods were applied to predict the four different emotions based on the heart rate-relevant information. To predict four different emotions, RF also showed a modest area under the receiver operating characteristic curve (AUC-ROC) of 0.70. CVRR, RMSSD, SDNN, high frequency (HF), and low frequency (LF) mostly contributed to the predictions. GBT displayed the second highest AUC (0.69). Comprehensive analyses revealed the benefits of the prediction accuracy of the RF and GBT methods and were beneficial to establish models to predict emotions based on autonomic nervous system indicators. The results implicated SDNN, RMSSD, CVRR, LF, and HF as important parameters for the predictions.

  59. Estimation of the carrier frequencies and proportions of potential patients by detecting causative gene variants associated with autosomal recessive bone dysplasia using a whole-genome reference panel of Japanese individuals International-journal Peer-reviewed

    Shinichi Nagaoka, Yumi Yamaguchi-Kabata, Naomi Shiga, Masahito Tachibana, Jun Yasuda, Shu Tadaka, Gen Tamiya, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Jun Murotsuki, Masayuki Yamamoto, Nobuo Yaegashi, Junichi Sugawara

    Human Genome Variation　8　(1)　2-2　2021/01

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41439-020-00133-7 　

    eISSN： 2054-345X

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    <title>Abstract</title>Bone dysplasias are a group of rare hereditary diseases, with up to 436 disease types. Perinatal diagnosis is clinically important for adequate personalized management and counseling. There are no reports focused on pathogenic variants of bone dysplasias in the general population. In this study, we focused on autosomal recessive bone dysplasias. We identified pathogenic variants using whole-genome reference panel data from 3552 Japanese individuals. For the first time, we were able to estimate the carrier frequencies and the proportions of potential patients. For autosomal recessive bone dysplasias, we detected 198 pathogenic variants of 54 causative genes. We estimated the variant carrier frequencies and the proportions of potential patients with variants associated with four clinically important bone dysplasias: osteogenesis imperfecta (OI), hypophosphatasia (HPP), asphyxiating thoracic dysplasia (ATD), and Ellis–van Creveld syndrome (EvC). The proportions of potential patients with OI, ATD, and EvC based on pathogenic variants classified as “pathogenic” and “likely pathogenic” by InterVar were closer to the reported incidence rates in Japanese subjects. Furthermore, the proportions of potential patients with HPP variants classified as “pathogenic” and “likely pathogenic” in InterVar and “pathogenic” in ClinVar were closer to the reported incidence rates. For bone dysplasia, the findings of this study will provide a better understanding of the variant types and frequencies in the Japanese general population, and should be useful for clinical diagnosis, genetic counseling, and personalized medicine.

  60. Facial UV photo imaging for skin pigmentation assessment using conditional generative adversarial networks Peer-reviewed

    Kaname Kojima, Kosuke Shido, Gen Tamiya, Kenshi Yamasaki, Kengo Kinoshita, Setsuya Aiba

    Scientific Reports　11　(1)　1213　2021/01

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-020-79995-4 　

    eISSN： 2045-2322

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    <title>Abstract</title>Skin pigmentation is associated with skin damages and skin cancers, and ultraviolet (UV) photography is used as a minimally invasive mean for the assessment of pigmentation. Since UV photography equipment is not usually available in general practice, technologies emphasizing pigmentation in color photo images are desired for daily care. We propose a new method using conditional generative adversarial networks, named UV-photo Net, to generate synthetic UV images from color photo images. Evaluations using color and UV photo image pairs taken by a UV photography system demonstrated that pigment spots were well reproduced in synthetic UV images by UV-photo Net, and some of the reproduced pigment spots were difficult to be recognized in color photo images. In the pigment spot detection analysis, the rate of pigment spot areas in cheek regions for synthetic UV images was highly correlated with the rate for UV photo images (Pearson’s correlation coefficient 0.92). We also demonstrated that UV-photo Net was effective for floating up pigment spots for photo images taken by a smartphone camera. UV-photo Net enables an easy assessment of pigmentation from color photo images and will promote self-care of skin damages and early signs of skin cancers for preventive medicine.

  61. Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference International-journal Peer-reviewed

    Jun Takayama, Shu Tadaka, Kenji Yano, Fumiki Katsuoka, Chinatsu Gocho, Takamitsu Funayama, Satoshi Makino, Yasunobu Okamura, Atsuo Kikuchi, Sachiyo Sugimoto, Junko Kawashima, Akihito Otsuki, Mika Sakurai-Yageta, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Masayuki Yamamoto, Gen Tamiya

    Nature Communications　12　(1)　226-226　2021/01

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41467-020-20146-8 　

    eISSN： 2041-1723

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    <title>Abstract</title>The complete human genome sequence is used as a reference for next-generation sequencing analyses. However, some ethnic ancestries are under-represented in the reference genome (e.g., GRCh37) due to its bias toward European and African ancestries. Here, we perform de novo assembly of three Japanese male genomes using &gt; 100× Pacific Biosciences long reads and Bionano Genomics optical maps per sample. We integrate the genomes using the major allele for consensus and anchor the scaffolds using genetic and radiation hybrid maps to reconstruct each chromosome. The resulting genome sequence, JG1, is contiguous, accurate, and carries the Japanese major allele at most loci. We adopt JG1 as the reference for confirmatory exome re-analyses of seven rare-disease Japanese families and find that re-analysis using JG1 reduces total candidate variant calls versus GRCh37 while retaining disease-causing variants. These results suggest that integrating multiple genomes from a single population can aid genome analyses of that population.

  62. Artificial intelligence powered statistical genetics in biobanks International-journal Peer-reviewed

    Akira Narita, Masao Ueki, Gen Tamiya

    Journal of Human Genetics　66　(1)　61-65　2021/01

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s10038-020-0822-y 　

    ISSN： 1434-5161

    eISSN： 1435-232X

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    Large-scale, sometimes nationwide, prospective genomic cohorts biobanking rich biological specimens such as blood, urine and tissues, have been established and released their vast amount of data in several countries. These genetic and epidemiological resources are expected to allow investigators to disentangle genetic and environmental components conferring common complex diseases. There are, however, two major challenges to statistical genetics for this goal: small sample size-high dimensionality and multilayered-heterogenous endophenotypes. Rather counterintuitively, biobank data generally have small sample size relative to their data dimensionality consisting of genomic variation, lifestyle questionnaire, and sometimes their interaction. This is a widely acknowledged difficulty in data analysis, so-called "p»n problem" in statistics or "curse of dimensionality" in machine-learning field. On the other hand, we have too many measurements of individual health status, which are endophenotypes, such as health check-up data, images, psychological test scores in addition to metabolomics and proteomics data. These endophenotypes are rich but not so tractable because of their worsen dimensionality, and substantial correlation, sometimes confusing causation among them. We have tried to overcome the problems inherent to biobank data, using statistical machine-learning and deep-learning technologies.

  63. Identification of critical genetic variants associated with metabolic phenotypes of the Japanese population Peer-reviewed

    Seizo Koshiba, Ikuko N. Motoike, Daisuke Saigusa, Jin Inoue, Yuichi Aoki, Shu Tadaka, Matsuyuki Shirota, Fumiki Katsuoka, Gen Tamiya, Naoko Minegishi, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto

    Communications Biology　3　(1)　662　2020/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s42003-020-01383-5 　

    eISSN： 2399-3642

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    <title>Abstract</title> We performed a metabolome genome-wide association study for the Japanese population in the prospective cohort study of Tohoku Medical Megabank. By combining whole-genome sequencing and nontarget metabolome analyses, we identified a large number of novel associations between genetic variants and plasma metabolites. Of the identified metabolite-associated genes, approximately half have already been shown to be involved in various diseases. We identified metabolite-associated genes involved in the metabolism of xenobiotics, some of which are from intestinal microorganisms, indicating that the identified genetic variants also markedly influence the interaction between the host and symbiotic bacteria. We also identified five associations that appeared to be female-specific. A number of rare variants that influence metabolite levels were also found, and combinations of common and rare variants influenced the metabolite levels more profoundly. These results support our contention that metabolic phenotyping provides important insights into how genetic and environmental factors provoke human diseases.

  64. Machine learning to reveal hidden risk combinations for the trajectory of posttraumatic stress disorder symptoms Peer-reviewed

    Yuta Takahashi, Kazuki Yoshizoe, Masao Ueki, Gen Tamiya, Yu Zhiqian, Yusuke Utsumi, Atsushi Sakuma, Koji Tsuda, Atsushi Hozawa, Ichiro Tsuji, Hiroaki Tomita

    Scientific Reports　10　(1)　21726　2020/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41598-020-78966-z 　

    eISSN： 2045-2322

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    <title>Abstract</title>The nature of the recovery process of posttraumatic stress disorder (PTSD) symptoms is multifactorial. The Massive Parallel Limitless-Arity Multiple-testing Procedure (MP-LAMP), which was developed to detect significant combinational risk factors comprehensively, was utilized to reveal hidden combinational risk factors to explain the long-term trajectory of the PTSD symptoms. In 624 population-based subjects severely affected by the Great East Japan Earthquake, 61 potential risk factors encompassing sociodemographics, lifestyle, and traumatic experiences were analyzed by MP-LAMP regarding combinational associations with the trajectory of PTSD symptoms, as evaluated by the Impact of Event Scale-Revised score after eight years adjusted by the baseline score. The comprehensive combinational analysis detected 56 significant combinational risk factors, including 15 independent variables, although the conventional bivariate analysis between single risk factors and the trajectory detected no significant risk factors. The strongest association was observed with the combination of short resting time, short walking time, unemployment, and evacuation without preparation (adjusted <italic>P</italic> value = 2.2 × 10−4, and raw <italic>P</italic> value = 3.1 × 10−9). Although short resting time had no association with the poor trajectory, it had a significant interaction with short walking time (<italic>P</italic> value = 1.2 × 10−3), which was further strengthened by the other two components (<italic>P</italic> value = 9.7 × 10−5). Likewise, components that were not associated with a poor trajectory in bivariate analysis were included in every observed significant risk combination due to their interactions with other components. Comprehensive combination detection by MP-LAMP is essential for explaining multifactorial psychiatric symptoms by revealing the hidden combinations of risk factors.

  65. Machine learning for effectively avoiding overfitting is a crucial strategy for the genetic prediction of polygenic psychiatric phenotypes Peer-reviewed

    Yuta Takahashi, Masao Ueki, Gen Tamiya, Soichi Ogishima, Kengo Kinoshita, Atsushi Hozawa, Naoko Minegishi, Fuji Nagami, Kentaro Fukumoto, Kotaro Otsuka, Kozo Tanno, Kiyomi Sakata, Atsushi Shimizu, Makoto Sasaki, Kenji Sobue, Shigeo Kure, Masayuki Yamamoto, Hiroaki Tomita

    Translational Psychiatry　10　(1)　294　2020/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41398-020-00957-5 　

    eISSN： 2158-3188

  66. Clustering by phenotype and genome-wide association study in autism Peer-reviewed

    Akira Narita, Masato Nagai, Satoshi Mizuno, Soichi Ogishima, Gen Tamiya, Masao Ueki, Rieko Sakurai, Satoshi Makino, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Hiroko Matsubara, Yasutaka Kuniyoshi, Keiko Murakami, Fumihiko Ueno, Aoi Noda, Tomoko Kobayashi, Mika Kobayashi, Takuma Usuzaki, Hisashi Ohseto, Atsushi Hozawa, Masahiro Kikuya, Hirohito Metoki, Shigeo Kure, Shinichi Kuriyama

    Translational Psychiatry　10　(1)　290　2020/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41398-020-00951-x 　

    eISSN： 2158-3188

  67. Improved metabolomic data-based prediction of depressive symptoms using nonlinear machine learning with feature selection Peer-reviewed

    Yuta Takahashi, Masao Ueki, Makoto Yamada, Gen Tamiya, Ikuko N. Motoike, Daisuke Saigusa, Miyuki Sakurai, Fuji Nagami, Soichi Ogishima, Seizo Koshiba, Kengo Kinoshita, Masayuki Yamamoto, Hiroaki Tomita

    Translational Psychiatry　10　(1)　157　2020/12

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1038/s41398-020-0831-9 　

    eISSN： 2158-3188

  68. jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population International-journal Peer-reviewed

    Shu Tadaka, Eiji Hishinuma, Shohei Komaki, Ikuko N Motoike, Junko Kawashima, Daisuke Saigusa, Jin Inoue, Jun Takayama, Yasunobu Okamura, Yuichi Aoki, Matsuyuki Shirota, Akihito Otsuki, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

    Nucleic Acids Research　49　(D1)　D536-D544　2020/11/12

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/nar/gkaa1034 　

    ISSN： 0305-1048

    eISSN： 1362-4962

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    <title>Abstract</title> In the Tohoku Medical Megabank project, genome and omics analyses of participants in two cohort studies were performed. A part of the data is available at the Japanese Multi Omics Reference Panel (jMorp; https://jmorp.megabank.tohoku.ac.jp) as a web-based database, as reported in our previous manuscript published in Nucleic Acid Research in 2018. At that time, jMorp mainly consisted of metabolome data; however, now genome, methylome, and transcriptome data have been integrated in addition to the enhancement of the number of samples for the metabolome data. For genomic data, jMorp provides a Japanese reference sequence obtained using de novo assembly of sequences from three Japanese individuals and allele frequencies obtained using whole-genome sequencing of 8,380 Japanese individuals. In addition, the omics data include methylome and transcriptome data from ∼300 samples and distribution of concentrations of more than 755 metabolites obtained using high-throughput nuclear magnetic resonance and high-sensitivity mass spectrometry. In summary, jMorp now provides four different kinds of omics data (genome, methylome, transcriptome, and metabolome), with a user-friendly web interface. This will be a useful scientific data resource on the general population for the discovery of disease biomarkers and personalized disease prevention and early diagnosis.

  69. A genotype imputation method for de-identified haplotype reference information by using recurrent neural network International-journal Peer-reviewed

    Kaname Kojima, Shu Tadaka, Fumiki Katsuoka, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

    PLOS Computational Biology　16　(10)　e1008207-e1008207　2020/10/01

    Publisher: Public Library of Science (PLoS)

    DOI： 10.1371/journal.pcbi.1008207 　

    eISSN： 1553-7358

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    Genotype imputation estimates the genotypes of unobserved variants using the genotype data of other observed variants based on a collection of haplotypes for thousands of individuals, which is known as a haplotype reference panel. In general, more accurate imputation results were obtained using a larger size of haplotype reference panel. Most of the existing genotype imputation methods explicitly require the haplotype reference panel in precise form, but the accessibility of haplotype data is often limited, due to the requirement of agreements from the donors. Since de-identified information such as summary statistics or model parameters can be used publicly, imputation methods using de-identified haplotype reference information might be useful to enhance the quality of imputation results under the condition where the access of the haplotype data is limited. In this study, we proposed a novel imputation method that handles the reference panel as its model parameters by using bidirectional recurrent neural network (RNN). The model parameters are presented in the form of de-identified information from which the restoration of the genotype data at the individual-level is almost impossible. We demonstrated that the proposed method provides comparable imputation accuracy when compared with the existing imputation methods using haplotype datasets from the 1000 Genomes Project (1KGP) and the Haplotype Reference Consortium. We also considered a scenario where a subset of haplotypes is made available only in de-identified form for the haplotype reference panel. In the evaluation using the 1KGP dataset under the scenario, the imputation accuracy of the proposed method is much higher than that of the existing imputation methods. We therefore conclude that our RNN-based method is quite promising to further promote the data-sharing of sensitive genome data under the recent movement for the protection of individuals' privacy.

  70. Maternal Baseline Characteristics and Perinatal Outcomes: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study Peer-reviewed

    Junichi Sugawara, Mami Ishikuro, Taku Obara, Tomomi Onuma, Keiko Murakami, Masahiro Kikuya, Fumihiko Ueno, Aoi Noda, Satoshi Mizuno, Tomoko Kobayashi, Yohei Hamanaka, Kichiya Suzuki, Eiichi Kodama, Naho Tsuchiya, Akira Uruno, Yoichi Suzuki, Osamu Tanabe, Hideyasu Kiyomoto, Akito Tsuboi, Atsushi Shimizu, Seizo Koshiba, Naoko Minegishi, Soichi Ogishima, Gen Tamiya, Hirohito Metoki, Atsushi Hozawa, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Shinichi Kuriyama, Masayuki Yamamoto

    Journal of Epidemiology　2020/10

    Publisher: Japan Epidemiological Association

    DOI： 10.2188/jea.je20200338 　

    ISSN： 0917-5040

    eISSN： 1349-9092

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    BACKGROUND: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants. METHODS: Expectant mothers living in Miyagi prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group. RESULTS: A total of 23 406 pregnancies involving 23 730 fetuses resulted in 23 143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes and hypertensive disorders of pregnancy. CONCLUSIONS: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.

  71. Endogenization and excision of human herpesvirus 6 in human genomes. International-journal Peer-reviewed

    Xiaoxi Liu, Shunichi Kosugi, Rie Koide, Yoshiki Kawamura, Jumpei Ito, Hiroki Miura, Nana Matoba, Motomichi Matsuzaki, Masashi Fujita, Anselmo Jiro Kamada, Hidewaki Nakagawa, Gen Tamiya, Koichi Matsuda, Yoshinori Murakami, Michiaki Kubo, Amr Aswad, Kei Sato, Yukihide Momozawa, Jun Ohashi, Chikashi Terao, Tetsushi Yoshikawa, Nicholas F Parrish, Yoichiro Kamatani

    PLoS genetics　16　(8)　e1008915-e1008915　2020/08

    Publisher: Public Library of Science (PLoS)

    DOI： 10.1371/journal.pgen.1008915 　

    eISSN： 1553-7404

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    Sequences homologous to human herpesvirus 6 (HHV-6) are integrated within the nuclear genome of about 1% of humans, but it is not clear how this came about. It is also uncertain whether integrated HHV-6 can reactivate into an infectious virus. HHV-6 integrates into telomeres, and this has recently been associated with polymorphisms affecting MOV10L1. MOV10L1 is located on the subtelomere of chromosome 22q (chr22q) and is required to make PIWI-interacting RNAs (piRNAs). As piRNAs block germline integration of transposons, piRNA-mediated repression of HHV-6 integration has been proposed to explain this association. In vitro, recombination of the HHV-6 genome along its terminal direct repeats (DRs) leads to excision from the telomere and viral reactivation, but the expected "solo-DR scar" has not been described in vivo. Here we screened for integrated HHV-6 in 7,485 Japanese subjects using whole-genome sequencing (WGS). Integrated HHV-6 was associated with polymorphisms on chr22q. However, in contrast to prior work, we find that the reported MOV10L1 polymorphism is physically linked to an ancient endogenous HHV-6A variant integrated into the telomere of chr22q in East Asians. Unexpectedly, an HHV-6B variant has also endogenized in chr22q; two endogenous HHV-6 variants at this locus thus account for 72% of all integrated HHV-6 in Japan. We also report human genomes carrying only one portion of the HHV-6B genome, a solo-DR, supporting in vivo excision and possible viral reactivation. Together these results explain the recently-reported association between integrated HHV-6 and MOV10L1/piRNAs, suggest potential exaptation of HHV-6 in its coevolution with human chr22q, and clarify the evolution and risk of reactivation of the only intact (non-retro)viral genome known to be present in human germlines.

  72. Genome-wide association study identifies new loci for albuminuria in the Japanese population. Peer-reviewed

    Hiroshi Okuda, Koji Okamoto, Michiaki Abe, Kota Ishizawa, Satoshi Makino, Osamu Tanabe, Junichi Sugawara, Atsushi Hozawa, Kozo Tanno, Makoto Sasaki, Gen Tamiya, Masayuki Yamamoto, Sadayoshi Ito, Tadashi Ishii

    Clinical and experimental nephrology　24　(8)　1-9　2020/08

    Publisher: Springer Science and Business Media LLC

    DOI： 10.1007/s10157-020-01884-x 　

    ISSN： 1342-1751

    eISSN： 1437-7799

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    BACKGROUND: Urinary albumin excretion (UAE) is a risk factor for cardiovascular diseases, metabolic syndrome, chronic kidney disease, etc. Only a few genome-wide association studies (GWAS) for UAE have been conducted in the European population, but not in the Asian population. Here we conducted GWAS and identified several candidate genes harboring single nucleotide polymorphisms (SNPs) responsible for UAE in the Japanese population. METHODS: We conducted GWAS for UAE in 7805 individuals of Asian ancestry from health-survey data collected by Tohoku Medical Megabank Organization (ToMMo) and Iwate Tohoku Medical Megabank Organization (IMM). The SNP genotype data were obtained with a SNP microarray. After imputation using a haplotype panel consisting of 2000 genome sequencing, 4,962,728 SNP markers were used for the GWAS. RESULTS: Eighteen SNPs at 14 loci (GRM7, EXOC1/NMU, LPA, STEAP1B/RAPGEF5, SEMA3D, PRKAG2, TRIQK, SERTM1, TPT1-AS1, OR5AU1, TSHR, FMN1/RYR3, COPRS, and BRD1) were associated with UAE in the Japanese individuals. A locus with particularly strong associations was observed on TSHR, chromosome 14 [rs116622332 (p = 3.99 × 10-10)]. CONCLUSION: In this study, we successfully identified UAE-associated variant loci in the Japanese population. Further study is required to confirm this association.

  73. Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): rationale, progress and perspective. International-journal Peer-reviewed

    Shinichi Kuriyama, Hirohito Metoki, Masahiro Kikuya, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Masato Nagai, Hiroko Matsubara, Tomoko Kobayashi, Junichi Sugawara, Gen Tamiya, Atsushi Hozawa, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Akira Narita, Mana Kogure, Takumi Hirata, Ichiro Tsuji, Fuji Nagami, Nobuo Fuse, Tomohiko Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Yoichi Suzuki, Noriko Osumi, Keiko Nakayama, Kiyoshi Ito, Shinichi Egawa, Koichi Chida, Eiichi Kodama, Hideyasu Kiyomoto, Tadashi Ishii, Akito Tsuboi, Hiroaki Tomita, Yasuyuki Taki, Hiroshi Kawame, Kichiya Suzuki, Naoto Ishii, Soichi Ogishima, Satoshi Mizuno, Takako Takai-Igarashi, Naoko Minegishi, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Osamu Tanabe, Seizo Koshiba, Hiroaki Hashizume, Hozumi Motohashi, Teiji Tominaga, Sadayoshi Ito, Kozo Tanno, Kiyomi Sakata, Atsushi Shimizu, Jiro Hitomi, Makoto Sasaki, Kengo Kinoshita, Hiroshi Tanaka, Tadao Kobayashi, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto

    International journal of epidemiology　49　(1)　18-19　2020/02/01

    DOI： 10.1093/ije/dyz169 　

  74. Study profile of The Tohoku Medical Megabank Community-Based Cohort Study. Peer-reviewed

    Atsushi Hozawa, Kozo Tanno, Naoki Nakaya, Tomohiro Nakamura, Naho Tsuchiya, Takumi Hirata, Akira Narita, Mana Kogure, Kotaro Nochioka, Ryohei Sasaki, Nobuyuki Takanashi, Kotaro Otsuka, Kiyomi Sakata, Shinichi Kuriyama, Masahiro Kikuya, Osamu Tanabe, Junichi Sugawara, Kichiya Suzuki, Yoichi Suzuki, Eiichi N Kodama, Nobuo Fuse, Hideyasu Kiyomoto, Hiroaki Tomita, Akira Uruno, Yohei Hamanaka, Hirohito Metoki, Mami Ishikuro, Taku Obara, Tomoko Kobayashi, Kazuyuki Kitatani, Takako Takai-Igarashi, Soichi Ogishima, Mamoru Satoh, Hideki Ohmomo, Akito Tsuboi, Shinichi Egawa, Tadashi Ishii, Kiyoshi Ito, Sadayoshi Ito, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Masao Nagasaki, Kazuhiko Igarashi, Seizo Koshiba, Ritsuko Shimizu, Gen Tamiya, Keiko Nakayama, Hozumi Motohashi, Jun Yasuda, Atsushi Shimizu, Tsuyoshi Hachiya, Yuh Shiwa, Teiji Tominaga, Hiroshi Tanaka, Kotaro Oyama, Ryoichi Tanaka, Hiroshi Kawame, Akimune Fukushima, Yasushi Ishigaki, Tomoharu Tokutomi, Noriko Osumi, Tadao Kobayashi, Fuji Nagami, Hiroaki Hashizume, Tomohiro Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Ryujin Endo, Satoshi Nishizuka, Ichiro Tsuji, Jiro Hitomi, Motoyuki Nakamura, Kuniaki Ogasawara, Nobuo Yaegashi, Kengo Kinoshita, Shigeo Kure, Akio Sakai, Seiichiro Kobayashi, Kenji Sobue, Makoto Sasaki, Masayuki Yamamoto

    Journal of epidemiology　31　(1)　65-76　2020/01/11

    DOI： 10.2188/jea.JE20190271 　

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    BackgroundWe established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environmental interactions on the incidence of major diseases such as cancer and cardiovascular diseases.MethodsWe asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria was aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), for example, carotid echography, calcaneal ultrasound bone mineral density, and so on. All participants agreed to measure genome information and to distribute their information widely.ResultsAs a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants with Type 1 survey were more likely to have psychological distress than those of Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents regardless of sex.ConclusionThis cohort comprised large sample size and it contains information on disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

  75. Design and Progress of Oral Health Examinations in the Tohoku Medical Megabank Project Peer-reviewed

    Akito Tsuboi, Hiroyuki Matsui, Naru Shiraishi, Takahisa Murakami, Akihito Otsuki, Junko Kawashima, Tomomi Kiyama, Toru Tamahara, Maki Goto, Shihoko Koyama, Junichi Sugawara, Eiichi N. Kodama, Hirohito Metoki, Atsushi Hozawa, Shinichi Kuriyama, Hiroaki Tomita, Masahiro Kikuya, Naoko Minegishi, Kichiya Suzuki, Seizo Koshiba, Gen Tamiya, Nobuo Fuse, Yuichi Aoki, Takako Takai-Igarashi, Soichi Ogishima, Tomohiro Nakamura, Mika Sakurai-Yageta, Fuji Nagami, Kengo Kinoshita, Shigeo Kure, Ritsuko Shimizu, Keiichi Sasaki, Masayuki Yamamoto

    The Tohoku Journal of Experimental Medicine　251　(2)　97-115　2020

    Publisher: Tohoku University Medical Press

    DOI： 10.1620/tjem.251.97 　

    ISSN： 0040-8727

    eISSN： 1349-3329

  76. Automated acquisition of explainable knowledge from unannotated histopathology images. International-journal Peer-reviewed

    Yoichiro Yamamoto, Toyonori Tsuzuki, Jun Akatsuka, Masao Ueki, Hiromu Morikawa, Yasushi Numata, Taishi Takahara, Takuji Tsuyuki, Kotaro Tsutsumi, Ryuto Nakazawa, Akira Shimizu, Ichiro Maeda, Shinichi Tsuchiya, Hiroyuki Kanno, Yukihiro Kondo, Manabu Fukumoto, Gen Tamiya, Naonori Ueda, Go Kimura

    Nature communications　10　(1)　5642-5642　2019/12/18

    DOI： 10.1038/s41467-019-13647-8 　

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    Deep learning algorithms have been successfully used in medical image classification. In the next stage, the technology of acquiring explainable knowledge from medical images is highly desired. Here we show that deep learning algorithm enables automated acquisition of explainable features from diagnostic annotation-free histopathology images. We compare the prediction accuracy of prostate cancer recurrence using our algorithm-generated features with that of diagnosis by expert pathologists using established criteria on 13,188 whole-mount pathology images consisting of over 86 billion image patches. Our method not only reveals findings established by humans but also features that have not been recognized, showing higher accuracy than human in prognostic prediction. Combining both our algorithm-generated features and human-established criteria predicts the recurrence more accurately than using either method alone. We confirm robustness of our method using external validation datasets including 2276 pathology images. This study opens up fields of machine learning analysis for discovering uncharted knowledge.

  77. Illuminating Clues of Cancer Buried in Prostate MR Image: Deep Learning and Expert Approaches. International-journal Peer-reviewed

    Jun Akatsuka, Yoichiro Yamamoto, Tetsuro Sekine, Yasushi Numata, Hiromu Morikawa, Kotaro Tsutsumi, Masato Yanagi, Yuki Endo, Hayato Takeda, Tatsuro Hayashi, Masao Ueki, Gen Tamiya, Ichiro Maeda, Manabu Fukumoto, Akira Shimizu, Toyonori Tsuzuki, Go Kimura, Yukihiro Kondo

    Biomolecules　9　(11)　E673　2019/10/30

    DOI： 10.3390/biom9110673 　

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    Deep learning algorithms have achieved great success in cancer image classification. However, it is imperative to understand the differences between the deep learning and human approaches. Using an explainable model, we aimed to compare the deep learning-focused regions of magnetic resonance (MR) images with cancerous locations identified by radiologists and pathologists. First, 307 prostate MR images were classified using a well-established deep neural network without locational information of cancers. Subsequently, we assessed whether the deep learning-focused regions overlapped the radiologist-identified targets. Furthermore, pathologists provided histopathological diagnoses on 896 pathological images, and we compared the deep learning-focused regions with the genuine cancer locations through 3D reconstruction of pathological images. The area under the curve (AUC) for MR images classification was sufficiently high (AUC = 0.90, 95% confidence interval 0.87-0.94). Deep learning-focused regions overlapped radiologist-identified targets by 70.5% and pathologist-identified cancer locations by 72.1%. Lymphocyte aggregation and dilated prostatic ducts were observed in non-cancerous regions focused by deep learning. Deep learning algorithms can achieve highly accurate image classification without necessarily identifying radiological targets or cancer locations. Deep learning may find clues that can help a clinical diagnosis even if the cancer is not visible.

  78. GWAS with principal component analysis identifies a gene comprehensively controlling rice architecture. International-journal Peer-reviewed

    Yano K, Morinaka Y, Wang F, Huang P, Takehara S, Hirai T, Ito A, Koketsu E, Kawamura M, Kotake K, Yoshida S, Endo M, Tamiya G, Kitano H, Ueguchi-Tanaka M, Hirano K, Matsuoka M

    Proc Natl Acad Sci USA　116　(42)　21262-21267　2019/10

    DOI： 10.1073/pnas.1904964116 　

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    Elucidation of the genetic control of rice architecture is crucial due to the global demand for high crop yields. Rice architecture is a complex trait affected by plant height, tillering, and panicle morphology. In this study, principal component analysis (PCA) on 8 typical traits related to plant architecture revealed that the first principal component (PC), PC1, provided the most information on traits that determine rice architecture. A genome-wide association study (GWAS) using PC1 as a dependent variable was used to isolate a gene encoding rice, SPINDLY (OsSPY), that activates the gibberellin (GA) signal suppression protein SLR1. The effect of GA signaling on the regulation of rice architecture was confirmed in 9 types of isogenic plant having different levels of GA responsiveness. Further population genetics analysis demonstrated that the functional allele of OsSPY associated with semidwarfism and small panicles was selected in the process of rice breeding. In summary, the use of PCA in GWAS will aid in uncovering genes involved in traits with complex characteristics.

  79. Establishment of Integrated Biobank for Precision Medicine and Personalized Healthcare: The Tohoku Medical Megabank Project. Peer-reviewed

    Fuse N, Sakurai-YagetaM, Katsuoka F, Danjoh I, Shimizu R, Tamiya G, Nagami F, Kawame H, Higuchi S, Kinoshita K, Kure S, Yamamoto M

    JMA Journal　2　(2)　113-122　2019/09

    DOI： 10.31662/jmaj.2019-0014 　

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    The Tohoku Medical Megabank (TMM) project was established to provide creative reconstruction of the Tohoku area that suffered from a huge earthquake and ensuing tsunami (the Great East Japan Earthquake, GEJE). TMM aims to establish two large-scale genome cohorts and an integrated biobank managing biospecimen and related information. It supports community medicine by establishing next-generation medical systems through a combination of the prospective genome cohort studies with a total of 150,000 participants and genomic medicine. The strategies for genome analyses in TMM are to develop an elaborate genome reference panel by means of high-fidelity Japanese whole-genome sequence, to design custom single nucleotide polymorphism (SNP) arrays based on the reference panel, and to obtain genotype data for all the TMM cohort participants subsequently. Disease-associated genomic information and omics data, including metabolomics and microbiome analysis, provide an essential platform for precision medicine and personalized healthcare (PHC). Ethical, legal, and social issues (ELSI) and education are important for implementing genomic medicine. The major considerations of ELSI regarding each participant of the cohort studies are the respect for the autonomy and the protection of privacies. Moreover, developing and provide human resources not only for the TMM project but also for the social implementation of precision medicine and PHC is required. We started a pilot study of the return of genomic results for familial hypercholesterolemia (FH) as a target disease. TMM aims to establish solid platforms that support precision medicine and PHC based on the genomic and omics information and environmental and lifestyle factors of the individuals, which is one of the most advanced medical care beyond the evidenced-based medicine in the near future.

  80. In Vivo Expression of NUP93 and Its Alteration by NUP93 Mutations Causing Focal Segmental Glomerulosclerosis. International-journal Peer-reviewed

    Taeko Hashimoto, Yutaka Harita, Keiichi Takizawa, Seiya Urae, Kiyonobu Ishizuka, Kenichiro Miura, Shigeru Horita, Daisuke Ogino, Gen Tamiya, Hideki Ishida, Tetsuo Mitsui, Kiyoshi Hayasaka, Motoshi Hattori

    Kidney international reports　4　(9)　1312-1322　2019/09

    DOI： 10.1016/j.ekir.2019.05.1157 　

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    Introduction: Mutations in genes encoding nucleoporins (NUPs; components of nuclear pore complexes [NPCs]), such as NUP93, have been reported to cause steroid-resistant nephrotic syndrome (SRNS) or focal segmental glomerulosclerosis (FSGS), which often progresses to end-stage renal disease (ESRD) in childhood. The expression of NUP93 in renal or extrarenal tissues, and the mechanism by which NUP93 mutations cause this renal phenotype, remain unclear. Methods: The expression of NUP93 in normal control kidney and in a patient with FSGS carrying NUP93 mutations was examined by immunofluorescence analysis. The expression of NUP93 in blood cells was analyzed by Western blot analysis. Results: Immunofluorescence analysis detected NUP93 expression in nuclei of all glomerular and tubulointerstitial cells in human kidneys. Whole-exome sequencing identified a compound heterozygous NUP93 mutation comprising a novel missense mutation p.Arg525Trp, and a previously reported mutation, p.Tyr629Cys, in a patient with FSGS that developed ESRD at the age of 6 years. In the patient's kidney, the intensity of NUP93 immunofluorescence was significantly decreased in the nuclei of both glomerular and extraglomerular cells. The expression of CD2-associated protein (CD2AP) and nephrin in the patient's podocytes was relatively intact. The amount of NUP93 protein was not significantly altered in the peripheral blood mononuclear cells of the patient. Conclusion: NUP93 is expressed in the nuclei of all the cell types of the human kidney. Altered NUP93 expression in glomerular cells as well as extraglomerular cells by NUP93 mutations may underlie the pathogenic mechanism of SRNS or FSGS.

  81. Outlier detection for questionnaire data in biobanks. Peer-reviewed

    Sakurai R, Ueki M, Makino S, Hozawa A, Kuriyama S, Takai-Igarashi T, Kinoshita K, Yamamoto M, Tamiya G

    Int J Epidemiol　48　(4)　1305-1315　2019/08

    Publisher: Oxford University Press (OUP)

    DOI： 10.1093/ije/dyz012 　

    ISSN： 0300-5771

    eISSN： 1464-3685

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    <title>Abstract</title> <sec> <title>Background</title> Biobanks increasingly collect, process and store omics with more conventional epidemiologic information necessitating considerable effort in data cleaning. An efficient outlier detection method that reduces manual labour is highly desirable. </sec> <sec> <title>Method</title> We develop an unsupervised machine-learning method for outlier detection, namely kurPCA, that uses principal component analysis combined with kurtosis to ascertain the existence of outliers. In addition, we propose a novel regression adjustment approach to improve detection, namely the regression adjustment for data by systematic missing patterns (RAMP). </sec> <sec> <title>Result</title> Application to epidemiological record data in a large-scale biobank (Tohoku Medical Megabank Organization, Japan) shows that a combination of kurPCA and RAMP effectively detects known errors or inconsistent patterns. </sec> <sec> <title>Conclusions</title> We confirm through the results of the simulation and the application that our methods showed good performance. The proposed methods are useful for many practical analysis scenarios. </sec>

  82. Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies. Peer-reviewed

    Ueki M, Fujii M, Tamiya G

    PLoS ONE　14　(7)　e0219825　2019/07

    DOI： 10.1371/journal.pone.0219825 　

  83. Susceptibility Loci for Tanning Ability in the Japanese Population Identified by a Genome-Wide Association Study from the Tohoku Medical Megabank Project Cohort Study. Peer-reviewed

    Shido K, Kojima K, Yamasaki K, Hozawa A, Tamiya G, Ogishima S, Minegishi N, Kawai Y, Tanno K, Suzuki Y, Nagasaki M, Aiba S

    J Invest Dermatol　139　(7)　1605-1608　2019/07

    DOI： 10.1016/j.jid.2019.01.015 　

    ISSN： 0022-202X

    eISSN： 1523-1747

  84. Respiratory resistance among adults in a population-based cohort study in Northern Japan. International-journal Peer-reviewed

    Miura E, Tsuchiya N, Igarashi Y, Arakawa R, Nikkuni E, Tamai T, Tabata M, Ohkouchi S, Irokawa T, Ogawa H, Takai-Igarashi T, Suzuki Y, Kuriyama S, Tamiya G, Hozawa A, Yamamoto M, Kurosawa H

    Respir Investig　57　(3)　274-281　2019/05

    DOI： 10.1016/j.resinv.2018.12.008 　

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    BACKGROUND: Forced oscillation technique (FOT) is a noninvasive method used to measure respiratory system resistance (Rrs) and reactance (Xrs) during quiet breathing, which has been extensively studied in clinical settings. The distribution of measured FOT values was previously assessed in a community-based cohort study. In this study, we aimed to confirm the distribution of measured FOT values in a different cohort in order to investigate the relationship between these values and patient clinical and biological data. METHODS: We reviewed FOT data and relevant patient clinical and biological information collected from the Community-Based Cohort Study (CommCohort Study), carried out between 2013 to 2016 as a part of the Tohoku Medical Megabank project (TMM). In total, 16,231 adults were enrolled in the study (Male/Female: 4886/11,345). RESULTS: Significant gender differences were observed in distributions of Rrs and Xrs values at 5 Hz (termed R5 and X5, respectively). R5 values in males were lower than those in females, while X5 values in males were slightly less negative. High R5 values were strongly associated with high BMI, short height, smoking status in males, high serum IgE level, and high peripheral blood eosinophil count. CONCLUSION: The present distribution values and their relation to clinical and biological data should provide useful insights for clinical settings and serve as a helpful guide in implementing FOT. Forced oscillation technique, respiratory system resistance, respiratory system reactance, gender difference, obesity.

  85. Growth impairment in individuals with citrin deficiency. International-journal Peer-reviewed

    Numakura C, Tamiya G, Ueki M, Okada T, Maisawa SI, Kojima-Ishii K, Murakami J, Horikawa R, Tokuhara D, Ito K, Adachi M, Abiko T, Mitsui T, Hayasaka K

    J Inherit Metab Dis　42　(3)　501-508　2019/05

    DOI： 10.1002/jimd.12051 　

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    Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia (CTLN2). Owing to a defect in the NADH-shuttle, citrin deficiency impairs hepatic glycolysis and de novo lipogenesis leading to hepatic energy deficit. To investigate the physiological role of citrin, we studied the growth of 111 NICCD-affected subjects (51 males and 60 females) and 12 NICCD-unaffected subjects (five males and seven females), including the body weight, height, and genotype. We constructed growth charts using the lambda-mu-sigma (LMS) method. The NICCD-affected subjects showed statistically significant growth impairment, including low birth weight and length, low body weight until 6 to 9 months of age, low height until 11 to 13 years of age, and low body weight in 7 to 12-year-old males and 8-year-old females. NICCD-unaffected subjects showed similar growth impairment, including low birth weight and height, and growth impairment during adolescence. In the third trimester, de novo lipogenesis is required for deposition of body fat and myelination of the developing central nervous system, and its impairment likely causes low birth weight and length. The growth rate is the highest during the first 6 months of life and slows down after 6 months of age, which is probably associated with the onset and recovery of NICCD. Adolescence is the second catch-up growth period, and the proportion and distribution of body fat change depending on age and sex. Characteristic growth impairment in citrin deficiency suggests a significant role of citrin in the catch-up growth via lipogenesis.

  86. The prevalence of GALM mutations that cause galactosemia: A database of functionally evaluated variants. International-journal Peer-reviewed

    Iwasawa S, Kikuchi A, Wada Y, Arai-Ichinoi N, Sakamoto O, Tamiya G, Kure S

    Mol Genet Metab　126　(4)　362-367　2019/04

    DOI： 10.1016/j.ymgme.2019.01.018 　

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    Galactosemia is a metabolic disorder that affects the appropriate metabolism of β-D-galactose. Deficiencies in three of the enzymes of the Leloir pathway, namely, GALT, GALK1, or GALE, are characterized as type I, II, and III galactosemia, respectively. Recently, we reported a novel type of galactosemia (type IV galactosemia) due to biallelic GALM mutations. Genetic diagnosis is indispensable for diagnosing GALM deficiency because no biochemical diagnosis method has been established. Given that apparently pathogenic variants in GALM are found in public variant databases, we presumed the presence of pathogenic variants that have not been reported. In this study, we explore 67 GALM variants that are prevalent in the ExAC database, including 57 missense variants, 7 stop-gain variants, 2 frameshift variants, and 1 splice-site variant. We performed an in vitro expression assay and an enzyme activity assay. Among the 66 variants except for 1 splice-site variant, 29 produced no or faint protein expression and were judged as pathogenic variants. Furthermore, the remaining 37 variants were evaluated by enzyme activity assay. Two showed mildly reduced enzyme activity and were classified as benign. Based on our study, the estimated incidence of GALM deficiency is 1:228,411 in all populations, 1:10,388 in the African population, and 1:80,747 in the Japanese population. Our GALM mutation database is useful for the genetic diagnosis of GALM deficiency.

  87. Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. Peer-reviewed

    Yamaguchi-Kabata Y, Yasuda J, Uruno A, Shimokawa K, Koshiba S, Suzuki Y, Fuse N, Kawame H, Tadaka S, Nagasaki M, Kojima K, Katsuoka F, Kumada K, Tanabe O, Tamiya G, Yaegashi N, Kinoshita K, Yamamoto M, Kure S, Tohoku Medical Megabank Project, Study Group

    Hum Genet　138　(4)　389-409　2019/04

  88. Genome analyses for the Tohoku Medical Megabank Project towards establishment of personalized healthcare. International-journal Peer-reviewed

    Jun Yasuda, Kengo Kinoshita, Fumiki Katsuoka, Inaho Danjoh, Mika Sakurai-Yageta, Ikuko N Motoike, Yoko Kuroki, Sakae Saito, Kaname Kojima, Matsuyuki Shirota, Daisuke Saigusa, Akihito Otsuki, Junko Kawashima, Yumi Yamaguchi-Kabata, Shu Tadaka, Yuichi Aoki, Takahiro Mimori, Kazuki Kumada, Jin Inoue, Satoshi Makino, Miho Kuriki, Nobuo Fuse, Seizo Koshiba, Osamu Tanabe, Masao Nagasaki, Gen Tamiya, Ritsuko Shimizu, Takako Takai-Igarashi, Soichi Ogishima, Atsushi Hozawa, Shinichi Kuriyama, Junichi Sugawara, Akito Tsuboi, Hideyasu Kiyomoto, Tadashi Ishii, Hiroaki Tomita, Naoko Minegishi, Yoichi Suzuki, Kichiya Suzuki, Hiroshi Kawame, Hiroshi Tanaka, Yasuyuki Taki, Nobuo Yaegashi, Shigeo Kure, Fuji Nagami, Kenjiro Kosaki, Yoichi Sutoh, Tsuyoshi Hachiya, Atsushi Shimizu, Makoto Sasaki, Masayuki Yamamoto

    Journal of biochemistry　165　(2)　139-158　2019/02/01

    DOI： 10.1093/jb/mvy096 　

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    Personalized healthcare (PHC) based on an individual's genetic make-up is one of the most advanced, yet feasible, forms of medical care. The Tohoku Medical Megabank (TMM) Project aims to combine population genomics, medical genetics and prospective cohort studies to develop a critical infrastructure for the establishment of PHC. To date, a TMM CommCohort (adult general population) and a TMM BirThree Cohort (birth+three-generation families) have conducted recruitments and baseline surveys. Genome analyses as part of the TMM Project will aid in the development of a high-fidelity whole-genome Japanese reference panel, in designing custom single-nucleotide polymorphism (SNP) arrays specific to Japanese, and in estimation of the biological significance of genetic variations through linked investigations of the cohorts. Whole-genome sequencing from >3,500 unrelated Japanese and establishment of a Japanese reference genome sequence from long-read data have been done. We next aim to obtain genotype data for all TMM cohort participants (>150,000) using our custom SNP arrays. These data will help identify disease-associated genomic signatures in the Japanese population, while genomic data from TMM BirThree Cohort participants will be used to improve the reference genome panel. Follow-up of the cohort participants will allow us to test the genetic markers and, consequently, contribute to the realization of PHC.

  89. 3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. International-journal Peer-reviewed

    Shu Tadaka, Fumiki Katsuoka, Masao Ueki, Kaname Kojima, Satoshi Makino, Sakae Saito, Akihito Otsuki, Chinatsu Gocho, Mika Sakurai-Yageta, Inaho Danjoh, Ikuko N Motoike, Yumi Yamaguchi-Kabata, Matsuyuki Shirota, Seizo Koshiba, Masao Nagasaki, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Atsushi Shimizu, Jun Yasuda, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

    Human genome variation　6　28-28　2019

    DOI： 10.1038/s41439-019-0059-5 　

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    The first step towards realizing personalized healthcare is to catalog the genetic variations in a population. Since the dissemination of individual-level genomic information is strictly controlled, it will be useful to construct population-level allele frequency panels with easy-to-use interfaces. In the Tohoku Medical Megabank Project, we sequenced nearly 4000 individuals from a Japanese population and constructed an allele frequency panel of 3552 individuals after removing related samples. The panel is called the 3.5KJPNv2. It was constructed by using a standard pipeline including the 1KGP and gnomAD algorithms to reduce technical biases and to allow comparisons to other populations. Our database is the first large-scale panel providing the frequencies of variants present on the X chromosome and on the mitochondria in the Japanese population. All the data are available on our original database at https://jmorp.megabank.tohoku.ac.jp.

  90. Potential identification of vitamin B6 responsiveness in autism spectrum disorder utilizing phenotype variables and machine learning methods. International-journal Peer-reviewed

    Taku Obara, Mami Ishikuro, Gen Tamiya, Masao Ueki, Chizuru Yamanaka, Satoshi Mizuno, Masahiro Kikuya, Hirohito Metoki, Hiroko Matsubara, Masato Nagai, Tomoko Kobayashi, Machiko Kamiyama, Mikako Watanabe, Kazuhiko Kakuta, Minami Ouchi, Aki Kurihara, Naru Fukuchi, Akihiro Yasuhara, Masumi Inagaki, Makiko Kaga, Shigeo Kure, Shinichi Kuriyama

    Scientific reports　8　(1)　14840-14840　2018/10/04

    DOI： 10.1038/s41598-018-33110-w 　

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    We investigated whether machine learning methods could potentially identify a subgroup of persons with autism spectrum disorder (ASD) who show vitamin B6 responsiveness by selected phenotype variables. We analyzed the existing data from our intervention study with 17 persons. First, we focused on signs and biomarkers that have been identified as candidates for vitamin B6 responsiveness indicators. Second, we conducted hypothesis testing among these selected variables and their combinations. Finally, we further investigated the results by conducting cluster analyses with two different algorithms, affinity propagation and k-medoids. Statistically significant variables for vitamin B6 responsiveness, including combination of hypersensitivity to sound and clumsiness, and plasma glutamine level, were included. As an a priori variable, the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) scores was also included. The affinity propagation analysis showed good classification of three potential vitamin B6-responsive persons with ASD. The k-medoids analysis also showed good classification. To our knowledge, this is the first study to attempt to identify subgroup of persons with ASD who show specific treatment responsiveness using selected phenotype variables. We applied machine learning methods to further investigate these variables' ability to identify this subgroup of ASD, even when only a small sample size was available.

  91. Regional genetic differences among Japanese populations and performance of genotype imputation using whole-genome reference panel of the Tohoku Medical Megabank Project. International-journal Peer-reviewed

    Jun Yasuda, Fumiki Katsuoka, Inaho Danjoh, Yosuke Kawai, Kaname Kojima, Masao Nagasaki, Sakae Saito, Yumi Yamaguchi-Kabata, Shu Tadaka, Ikuko N Motoike, Kazuki Kumada, Mika Sakurai-Yageta, Osamu Tanabe, Nobuo Fuse, Gen Tamiya, Koichiro Higasa, Fumihiko Matsuda, Nobufumi Yasuda, Motoki Iwasaki, Makoto Sasaki, Atsushi Shimizu, Kengo Kinoshita, Masayuki Yamamoto

    BMC genomics　19　(1)　551-551　2018/07/24

    DOI： 10.1186/s12864-018-4942-0 　

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    BACKGROUND: Genotype imputation from single-nucleotide polymorphism (SNP) genotype data using a haplotype reference panel consisting of thousands of unrelated individuals from populations of interest can help to identify strongly associated variants in genome-wide association studies. The Tohoku Medical Megabank (TMM) project was established to support the development of precision medicine, together with the whole-genome sequencing of 1070 human genomes from individuals in the Miyagi region (Northeast Japan) and the construction of the 1070 Japanese genome reference panel (1KJPN). Here, we investigated the performance of 1KJPN for genotype imputation of Japanese samples not included in the TMM project and compared it with other population reference panels. RESULTS: We found that the 1KJPN population was more similar to other Japanese populations, Nagahama (south-central Japan) and Aki (Shikoku Island), than to East Asian populations in the 1000 Genomes Project other than JPT, suggesting that the large-scale collection (more than 1000) of Japanese genomes from the Miyagi region covered many of the genetic variations of Japanese in mainland Japan. Moreover, 1KJPN outperformed the phase 3 reference panel of the 1000 Genomes Project (1KGPp3) for Japanese samples, and IKJPN showed similar imputation rates for the TMM and other Japanese samples for SNPs with minor allele frequencies (MAFs) higher than 1%. CONCLUSIONS: 1KJPN covered most of the variants found in the samples from areas of the Japanese mainland outside the Miyagi region, implying 1KJPN is representative of the Japanese population's genomes. 1KJPN and successive reference panels are useful genome reference panels for the mainland Japanese population. Importantly, the addition of whole genome sequences not included in the 1KJPN panel improved imputation efficiencies for SNPs with MAFs under 1% for samples from most regions of the Japanese archipelago.

  92. Ethylene-gibberellin signaling underlies adaptation of rice to periodic flooding Peer-reviewed

    Takeshi Kuroha, Keisuke Nagai, Rico Gamuyao, Diane R. Wang, Tomoyuki Furuta, Masanari Nakamori, Takuya Kitaoka, Keita Adachi, Anzu Minami, Yoshinao Mori, Kiyoshi Mashiguchi, Yoshiya Seto, Shinjiro Yamaguchi, Mikiko Kojima, Hitoshi Sakakibara, Jianzhong Wu, Kaworu Ebana, Nobutaka Mitsuda, Masaru Ohme-Takagi, Shuichi Yanagisawa, Masanori Yamasaki, Ryusuke Yokoyama, Kazuhiko Nishitani, Toshihiro Mochizuki, Gen Tamiya, Susan R. McCouch, Motoyuki Ashikari

    Science　361　(6398)　181-186　2018/07/13

    Publisher: American Association for the Advancement of Science (AAAS)

    DOI： 10.1126/science.aat1577 　

    ISSN： 0036-8075

    eISSN： 1095-9203

  93. Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. International-journal Peer-reviewed

    Seizo Koshiba, Ikuko Motoike, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Yasutake Katoh, Fumiki Katsuoka, Inaho Danjoh, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Soichi Ogishima, Nobuo Fuse, Shigeo Kure, Gen Tamiya, Osamu Tanabe, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto

    Genes to cells : devoted to molecular & cellular mechanisms　23　(6)　406-417　2018/06

    DOI： 10.1111/gtc.12588 　

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    Population-based prospective cohort studies are indispensable for modern medical research as they provide important knowledge on the influences of many kinds of genetic and environmental factors on the cause of disease. Although traditional cohort studies are mainly conducted using questionnaires and physical examinations, modern cohort studies incorporate omics and genomic approaches to obtain comprehensive physical information, including genetic information. Here, we report the design and midterm results of multi-omics analysis on population-based prospective cohort studies from the Tohoku Medical Megabank (TMM) Project. We have incorporated genomic and metabolomic studies in the TMM cohort study as both metabolome and genome analyses are suitable for high-throughput analysis of large-scale cohort samples. Moreover, an association study between the metabolome and genome show that metabolites are an important intermediate phenotype connecting genetic and lifestyle factors to physical and pathologic phenotypes. We apply our metabolome and genome analyses to large-scale cohort samples in the following studies.

  94. Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. International-journal Peer-reviewed

    Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

    Journal of human genetics　63　(2)　213-230　2018/02

    DOI： 10.1038/s10038-017-0347-1 　

    More details Close

    Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.

  95. Female Japanese quail visually differentiate testosterone-dependent male attractiveness for mating preferences. Peer-reviewed

    Hiyama G, Mizushima S, Matsuzaki M, Tobari Y, Choi JH, Ono T, Tsudzuki M, Makino S, Tamiya G, Tsukahara N, Sugita S, Sasanami T

    Sci Rep　8　(1)　10012　2018

    DOI： 10.1038/s41598-018-28368-z 　

    eISSN： 2045-2322

  96. Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6-TMC8 and SIX3-SIX2 loci associated with HbA(1c) Peer-reviewed

    Tsuyoshi Hachiya, Shohei Komaki, Yutaka Hasegawa, Hideki Ohmomo, Kozo Tanno, Atsushi Hozawa, Gen Tamiya, Masayuki Yamamoto, Kuniaki Ogasawara, Motoyuki Nakamura, Jiro Hitomi, Yasushi Ishigaki, Makoto Sasaki, Atsushi Shimizu

    SCIENTIFIC REPORTS　7　(1)　16147　2017/11

    DOI： 10.1038/s41598-017-16493-0 　

    ISSN： 2045-2322

  97. Detecting genetic association through shortest paths in a bidirected graph Peer-reviewed

    Masao Ueki, Yoshinori Kawasaki, Gen Tamiya

    GENETIC EPIDEMIOLOGY　41　(6)　481-497　2017/09

    DOI： 10.1002/gepi.22051 　

    ISSN： 0741-0395

    eISSN： 1098-2272

  98. Security controls in an integrated Biobank to protect privacy in data sharing: rationale and study design Peer-reviewed

    Takako Takai-Igarashi, Kengo Kinoshita, Masao Nagasaki, Soichi Ogishima, Naoki Nakamura, Sachiko Nagase, Satoshi Nagaie, Tomo Saito, Fuji Nagami, Naoko Minegishi, Yoichi Suzuki, Kichiya Suzuki, Hiroaki Hashizume, Shinichi Kuriyama, Atsushi Hozawa, Nobuo Yaegashi, Shigeo Kure, Gen Tamiya, Yoshio Kawaguchi, Hiroshi Tanaka, Masayuki Yamamoto

    BMC MEDICAL INFORMATICS AND DECISION MAKING　17　(1)　100　2017/07

    DOI： 10.1186/s12911-017-0494-5 　

    ISSN： 1472-6947

  99. Whole-exome sequencing confirmation of multiple MC1R variants associated with extensive freckles and red hair: Analysis of a Mongolian family Peer-reviewed

    Yuta Araki, Ken Okamura, Batmunkh Munkhbat, Gen Tamiya, Bujin Erdene-Ochir, Lkhasuren Nemekhbaatar, Yutaka Hozumi, Tamio Suzuki

    JOURNAL OF DERMATOLOGICAL SCIENCE　84　(2)　216-219　2016/11

    DOI： 10.1016/j.jdermsci.2016.08.009 　

    ISSN： 0923-1811

    eISSN： 1873-569X

  100. The Tohoku Medical Megabank Project: Design and Mission Peer-reviewed

    Shinichi Kuriyama, Nobuo Yaegashi, Fuji Nagami, Tomohiko Arai, Yoshio Kawaguchi, Noriko Osumi, Masaki Sakaida, Yoichi Suzuki, Keiko Nakayama, Hiroaki Hashizume, Gen Tamiya, Hiroshi Kawame, Kichiya Suzuki, Atsushi Hozawa, Naoki Nakaya, Masahiro Kikuya, Hirohito Metoki, Ichiro Tsuji, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Akito Tsuboi, Shinichi Egawa, Kiyoshi Ito, Koichi Chida, Tadashi Ishii, Hiroaki Tomita, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Seizo Koshiba, Kengo Kinoshita, Soichi Ogishima, Takako Takai-Igarashi, Teiji Tominaga, Osamu Tanabe, Noriaki Ohuchi, Toru Shimosegawa, Shigeo Kure, Hiroshi Tanaka, Sadayoshi Ito, Jiro Hitomi, Kozo Tanno, Motoyuki Nakamura, Kuniaki Ogasawara, Seiichiro Kobayashi, Kiyomi Sakata, Mamoru Satoh, Atsushi Shimizu, Makoto Sasaki, Ryujin Endo, Kenji Sobue, Masayuki Yamamoto

    JOURNAL OF EPIDEMIOLOGY　26　(9)　493-511　2016/09

    DOI： 10.2188/jea.JE20150268 　

    ISSN： 0917-5040

  101. Smooth-Threshold Multivariate Genetic Prediction with Unbiased Model Selection Peer-reviewed

    Masao Ueki, Gen Tamiya

    GENETIC EPIDEMIOLOGY　40　(3)　233-243　2016/04

    DOI： 10.1002/gepi.21958 　

    ISSN： 0741-0395

    eISSN： 1098-2272

  102. Analysis of the genes responsible for steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis in Japanese patients by whole-exome sequencing analysis Peer-reviewed

    Daisuke Ogino, Taeko Hashimoto, Motoshi Hattori, Noriko Sugawara, Yuko Akioka, Gen Tamiya, Satoshi Makino, Kentaro Toyota, Tetsuo Mitsui, Kiyoshi Hayasaka

    JOURNAL OF HUMAN GENETICS　61　(2)　137-141　2016/02

    DOI： 10.1038/jhg.2015.122 　

    ISSN： 1434-5161

    eISSN： 1435-232X

  103. Waardenburg syndrome type IIE in a Japanese patient caused by a novel missense mutation in the SOX10 gene Peer-reviewed

    Ken Okamura, Naoki Oiso, Gen Tamiya, Satoshi Makino, Daishi Tsujioka, Yuko Abe, Masakazu Kawaguchi, Yutaka Hozumi, Yoshikazu Shimomura, Tamio Suzuki

    JOURNAL OF DERMATOLOGY　42　(12)　1211-1212　2015/12

    DOI： 10.1111/1346-8138.13095 　

    ISSN： 0385-2407

    eISSN： 1346-8138

  104. Immunohistopathological analysis of frizzled-4-positive immature melanocytes from hair follicles of patients with Rhododenol-induced leukoderma Peer-reviewed

    Ken Okamura, Rintaro Ohe, Yuko Abe, Masao Ueki, Yutaka Hozumi, Gen Tamiya, Kayoko Matsunaga, Mitsunori Yamakawa, Tamio Suzuki

    JOURNAL OF DERMATOLOGICAL SCIENCE　80　(2)　156-158　2015/11

    DOI： 10.1016/j.jdermsci.2015.07.015 　

    ISSN： 0923-1811

    eISSN： 1873-569X

  105. Positive selection with diversity in oculocutaneous albinisms type 2 gene (OCA2) among Japanese Peer-reviewed

    Miwa Shimanuki, Yuko Abe, Gen Tamiya, Masao Ueki, Yutaka Hozumi, Tamio Suzuki

    PIGMENT CELL & MELANOMA RESEARCH　28　(2)　233-235　2015/03

    DOI： 10.1111/pcmr.12337 　

    ISSN： 1755-1471

    eISSN： 1755-148X

  106. Whole-exome sequencing confirmation of a novel heterozygous mutation in RUNX1 in a pregnant woman with platelet disorder Peer-reviewed

    Miyuki Obata, Seiji Tsutsumi, Satoshi Makino, Kanako Takahashi, Norikazu Watanabe, Takayuki Yoshida, Gen Tamiya, Hirohisa Kurachi

    PLATELETS　26　(4)　364-369　2015

    DOI： 10.3109/09537104.2014.912750 　

    ISSN： 0953-7104

    eISSN： 1369-1635

  107. Association of neonatal hyperbilirubinemia in breast-fed infants with UGT1A1 or SLCOs polymorphisms Peer-reviewed

    Hiroko Sato, Toshihiko Uchida, Kentaro Toyota, Tomohiro Nakamura, Gen Tamiya, Miyako Kanno, Taeko Hashimoto, Masashi Watanabe, Kuraaki Aoki, Kiyoshi Hayasaka

    JOURNAL OF HUMAN GENETICS　60　(1)　35-40　2015/01

    DOI： 10.1038/jhg.2014.98 　

    ISSN： 1434-5161

    eISSN： 1435-232X

  108. Likelihood ratio-based integrated personal risk assessment of type 2 diabetes Peer-reviewed

    Noriko Sato, Nay Chi Htun, Makoto Daimon, Gen Tamiya, Takeo Kato, Isao Kubota, Yoshiyuki Ueno, Hidetoshi Yamashita, Akira Fukao, Takamasa Kayama, Masaaki Muramatsu

    ENDOCRINE JOURNAL　61　(10)　967-988　2014/10

    DOI： 10.1507/endocrj.EJ14-0271 　

    ISSN： 0918-8959

    eISSN： 1348-4540

  109. A Mutation of COX6A1 Causes a Recessive Axonal or Mixed Form of Charcot-Marie-Tooth Disease Peer-reviewed

    Gen Tamiya, Satoshi Makino, Makiko Hayashi, Akiko Abe, Chikahiko Numakura, Masao Ueki, Atsushi Tanaka, Chizuru Ito, Kiyotaka Toshimori, Nobuhiro Ogawa, Tomoya Terashima, Hiroshi Maegawa, Daijiro Yanagisawa, Ikuo Tooyama, Masayoshi Tada, Osamu Onodera, Kiyoshi Hayasaka

    AMERICAN JOURNAL OF HUMAN GENETICS　95　(3)　294-300　2014/09

    DOI： 10.1016/j.ajhg.2014.07.013 　

    ISSN： 0002-9297

    eISSN： 1537-6605

  110. Variants in melanogenesis-related genes associate with skin cancer risk among Japanese populations Peer-reviewed

    Junko Yoshizawa, Yuko Abe, Naoki Oiso, Kazuyoshi Fukai, Yutaka Hozumi, Tomohiro Nakamura, Tomohiko Narita, Tomonori Motokawa, Kazumasa Wakamatsu, Shosuke Ito, Akira Kawada, Gen Tamiya, Tamio Suzuki

    JOURNAL OF DERMATOLOGY　41　(4)　296-302　2014/04

    DOI： 10.1111/1346-8138.12432 　

    ISSN： 0385-2407

    eISSN： 1346-8138

  111. Pleiotropic Effect of Common Variants at ABO Glycosyltranferase Locus in 9q32 on Plasma Levels of Pancreatic Lipase and Angiotensin Converting Enzyme Peer-reviewed

    Takamasa Kayama, Hidetoshi Yamashita, Akira Fukao, Isao Kubota, Takeo Kato, Chifumi Kitanaka, Shinya Sato, Yoshiyuki Ueno, Isao Kubota, Shinya Sato, Tsuneo Konta, Yoko Shibata, Tetsu Watanabe, Shuichi Abe, Takuya Miyamoto, Sumito Inoue, Takehiko Miyashita, Kazunobu Ichikawa, Tetsuro Shishido, Takanori Arimoto, Hiroki Takahashi, Satoshi Nishiyama, Ami Ikeda, Takeo Kato, Makoto Daimon, Toru Kawanami, Manabu Wada, Shigeki Arawaka, Hidetoshi Oizumi, Katsuro Kuro-Kawa, Shingi Susa, Yuichi Katou, Wataru Kameda, Shingo Koyama, Shigeru Karasawa, Chifumi Iseki, Yoshimi Takahashi, Chifumi Kitanaka, Yoshiyuki Ueno, Yoshiyuki Ueno, Sumio Kawata, Takafumi Saito, Naohiko Makino, Kazuo Okumoto, Hiroaki Haga, Takeshi Sato, Chikako Sato, Hisayoshi Watanabe, Yuko Nishise, Rika Ishii, Akiko Matsuda, Tomohiro Tozawa, Hidetoshi Yamashita, Kei Honma, Akira Fukao, Hiroto Narimatsu, Kyoko Shibata, Akiko Miura, Rina Inoue, Ai Numazawa, Kahori Kudo, Yoko Aita, Noriko Umezawa, Yuko Saito, Yumi Takahashi, Yuka Suzuki, Katsumi Otani, Atsushi Hozawa, Li Shao, Masatsugu Orui, Atsuko Kobayashi, Yuka Kanoya, Takiko Hosoya, Ikuko Suzuki, Mariko Otake, Yuko Morikagi, Akiko Sekimata, Manami Hiraka, Yumi Matsuda, Chika Sato, Yoko Takeda, Yoko Matsunami, Tatsuya Horie, Shiho Sato, Mizue Inoue, Kaoru Baba, Gen Tamiya, Masao Ueki, Tomohiro Nakamura, Gen Tamiya, Jamiyansuren Jambaldorj, Satoko Araki, Osamu Nakajima, Kazuei Takahashi, Kazuo Goto, Kimishige Ishizaka

    PLOS ONE　9　(2)　e55903　2014/02

    DOI： 10.1371/journal.pone.0055903 　

    ISSN： 1932-6203

  112. A Pollen Coat-Inducible Autoinhibited Ca2+-ATPase Expressed in Stigmatic Papilla Cells Is Required for Compatible Pollination in the Brassicaceae Peer-reviewed

    Megumi Iwano, Motoko Igarashi, Yoshiaki Tarutani, Pulla Kaothien-Nakayama, Hideki Nakayama, Hideki Moriyama, Ryo Yakabe, Tetsuyuki Entani, Hiroko Shimosato-Asano, Masao Ueki, Gen Tamiya, Seiji Takayama

    PLANT CELL　26　(2)　636-649　2014/02

    DOI： 10.1105/tpc.113.121350 　

    ISSN： 1040-4651

    eISSN： 1532-298X

  113. Gamete Attachment Requires GEX2 for Successful Fertilization in Arabidopsis Peer-reviewed

    Toshiyuki Mori, Tomoko Igawa, Gen Tamiya, Shin-ya Miyagishima, Frederic Berger

    CURRENT BIOLOGY　24　(2)　170-175　2014/01

    DOI： 10.1016/j.cub.2013.11.030 　

    ISSN： 0960-9822

    eISSN： 1879-0445

  114. Divergence of East Asians and Europeans Estimated Using Male- and Female-Specific Genetic Markers Peer-reviewed

    Yoshio Tateno, Tomoyoshi Komiyama, Toru Katoh, Batmunkh Munkhbat, Akira Oka, Yuko Haida, Hiroyuki Kobayashi, Gen Tamiya, Hidetoshi Inoko

    GENOME BIOLOGY AND EVOLUTION　6　(3)　466-473　2014

    DOI： 10.1093/gbe/evu027 　

    ISSN： 1759-6653

  115. Case of a Mongolian child with extensive Mongolian spots in mucopolysaccharidosis type VI: Identification of a novel mutation in the arylsulfatase B gene Peer-reviewed

    Ken Okamura, Batmunkh Munkhbat, Batbaatar Batchimeg, Gen Tamiya, Yutaka Hozumi, Tamio Suzuki

    JOURNAL OF DERMATOLOGY　40　(9)　758-+　2013/09

    DOI： 10.1111/1346-8138.12237 　

    ISSN： 0385-2407

    eISSN： 1346-8138

  116. Comparison of caregiver strain in Parkinson's disease between Yamagata, Japan, and Maryland, The United States Peer-reviewed

    Haruko Tanji, Shingo Koyama, Manabu Wada, Toru Kawanami, Keiji Kurita, Gen Tamiya, Naohiro Saito, Kyoko Suzuki, Takeo Kato, Karen E. Anderson, Ann L. Gruber-Baldini, Paul S. Fishman, Stephen G. Reich, William J. Weiner, Lisa M. Shulman

    PARKINSONISM & RELATED DISORDERS　19　(6)　628-633　2013/06

    DOI： 10.1016/j.parkreldis.2013.02.014 　

    ISSN： 1353-8020

    eISSN： 1873-5126

  117. A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy Peer-reviewed

    Kentaro Toyota, Taeko Hashimoto, Daisuke Ogino, Akira Matsunaga, Minoru Ito, Ikuto Masakane, Noriyuki Degawa, Hiroshi Sato, Sayuri Shirai, Kazuo Umetsu, Gen Tamiya, Takao Saito, Kiyoshi Hayasaka

    Journal of Human Genetics　58　(5)　254-258　2013/05

    DOI： 10.1038/jhg.2013.8 　

    ISSN： 1434-5161 1435-232X

  118. Association of melanogenesis genes with skin color variation among Japanese females Peer-reviewed

    Yuko Abe, Gen Tamiya, Tomohiro Nakamura, Yutaka Hozumi, Tamio Suzuki

    Journal of Dermatological Science　69　(2)　167-172　2013/02

    DOI： 10.1016/j.jdermsci.2012.10.016 　

    ISSN： 0923-1811 1873-569X

  119. Constructing a contemporary gene-environmental cohort : Study design of the Yamagata Molecular Epidemiological Cohort Study. Peer-reviewed

    Yamagata University, Genomic Cohort Consortium

    J Hum Genet　58　(1)　54-6　2013

    DOI： 10.1038/jhg.2012.128 　

  120. Association of breast-fed neonatal hyperbilirubinemia with UGT1A1 polymorphisms: 211G &gt; A (G71R) mutation becomes a risk factor under inadequate feeding Peer-reviewed

    Hiroko Sato, Toshihiko Uchida, Kentaro Toyota, Miyako Kanno, Taeko Hashimoto, Masashi Watanabe, Tomohiro Nakamura, Gen Tamiya, Kuraaki Aoki, Kiyoshi Hayasaka

    JOURNAL OF HUMAN GENETICS　58　(1)　7-10　2013/01

    DOI： 10.1038/jhg.2012.116 　

    ISSN： 1434-5161

  121. Generation of a Monoclonal Antibody Specifically Reacting with Neuron-specific TATA-Box Binding Protein-Associated Factor 1 (N-TAF1). Peer-reviewed

    Makino S, Masuda C, Ando S, Tamiya G, Tooyama I

    Antibodies　2　(1)　1-8　2013

    Publisher: MDPI AG

    DOI： 10.3390/antib2010001 　

    eISSN： 2073-4468

  122. The confounding effect of cryptic relatedness for environmental risks of systolic blood pressure on cohort studies. Peer-reviewed

    Shibata K, Hozawa A, Tamiya G, Ueki M, Nakamura T

    Mol Genet Genomic Med　1　(1)　45-53　2013

    DOI： 10.1002/mgg3.4 　

  123. HLA-A*0206 with TLR3 Polymorphisms Exerts More than Additive Effects in Stevens-Johnson Syndrome with Severe Ocular Surface Complications Peer-reviewed

    Mayumi Ueta, Katsushi Tokunaga, Chie Sotozono, Hiromi Sawai, Gen Tamiya, Tsutomu Inatomi, Shigeru Kinoshita

    PLOS ONE　7　(8)　e43650　2012/08

    DOI： 10.1371/journal.pone.0043650 　

    ISSN： 1932-6203

  124. Sustained expression of a neuron-specific isoform of the Taf1 gene in development stages and aging in mice Peer-reviewed

    Jamiyansuren Jambaldorj, Satoshi Makino, Batmunkh Munkhbat, Gen Tamiya

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　425　(2)　273-277　2012/08

    DOI： 10.1016/j.bbrc.2012.07.081 　

    ISSN： 0006-291X

  125. Epistatic interaction between Toll-like receptor 3 (TLR3) and prostaglandin E receptor 3 (PTGER3) genes Peer-reviewed

    Mayumi Ueta, Gen Tamiya, Katsushi Tokunaga, Chie Sotozono, Masao Ueki, Hiromi Sawai, Tsutomu Inatomi, Toshiyuki Matsuoka, Shizuo Akira, Shuh Narumiya, Kei Tashiro, Shigeru Kinoshita

    JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY　129　(5)　1413-1416　2012/05

    DOI： 10.1016/j.jaci.2012.01.069 　

    ISSN： 0091-6749

  126. Ultrahigh-dimensional variable selection method for whole-genome gene-gene interaction analysis Peer-reviewed

    Masao Ueki, Gen Tamiya

    BMC BIOINFORMATICS　13　(1)　72　2012/05

    DOI： 10.1186/1471-2105-13-72 　

    ISSN： 1471-2105

  127. UBR5 Gene Mutation Is Associated with Familial Adult Myoclonic Epilepsy in a Japanese Family. Peer-reviewed

    Kato T, Tamiya G, Koyama S, Nakamura T, Makino S, Arawaka S, Kawanami T, Tooyama I

    ISRN Neurol　2012　508308-4　2012

    Publisher: Hindawi Limited

    DOI： 10.5402/2012/508308 　

    eISSN： 2090-5513

    More details Close

    The causal gene(s) for familial adult myoclonic epilepsy (FAME) remains undetermined. To identify it, an exome analysis was performed for the proband in a Japanese FAME family. Of the 383 missense/nonsense variants examined, only c.5720G&gt;A mutation (p.Arg1907His) in the <italic>UBR5</italic> gene was found in all of the affected individuals in the family, but not in the nonaffected members. Such mutation was not found in any of the 85 healthy individuals in the same community nor in any of the 24 individuals of various ethnicities. The present study demonstrated an FAME-associated mutation in the <italic>UBR5</italic> gene, which is located close to the reported locus linked to Japanese FAME families.

  128. Polymorphism of proinflammatory cytokine genes and albuminuria in the Japanese general population: the Takahata study Peer-reviewed

    Yusuke Mashima, Tsuneo Konta, Kosuke Kudo, Kazuko Suzuki, Ami Ikeda, Kazunobu Ichikawa, Yoko Shibata, Tetsu Watanabe, Gen Tamiya, Takeo Kato, Sumio Kawata, Isao Kubota

    NEPHROLOGY DIALYSIS TRANSPLANTATION　26　(12)　3902-3907　2011/12

    DOI： 10.1093/ndt/gfr105 　

    ISSN： 0931-0509

  129. Impaired Glucose Metabolism Slows Executive Function Independent of Cerebral Ischemic Lesions in Japanese Elderly: The Takahata Study Peer-reviewed

    Yoshimi Takahashi, Chifumi Iseki, Manabu Wada, Tadasuke Momma, Masao Ueki, Toru Kawanami, Makoto Daimon, Kyoko Suzuki, Gen Tamiya, Takeo Kato

    INTERNAL MEDICINE　50　(16)　1671-1678　2011

    DOI： 10.2169/internalmedicine.50.4871 　

    ISSN： 0918-2918

  130. Identification of MICA as a Susceptibility Gene for Pulmonary Mycobacterium avium Complex Infection Peer-reviewed

    Junko Shojima, Goh Tanaka, Naoto Keicho, Gen Tamiya, Satoshi Ando, Akira Oka, Yoshikazu Inoue, Katsuhiro Suzuki, Mitsunori Sakatani, Masaji Okada, Nobuyuki Kobayashi, Emiko Toyota, Koichiro Kudo, Akira Kajiki, Hideaki Nagai, Atsuyuki Kurashima, Norihiro Oketani, Hiroshi Hayakawa, Tamiko Takemura, Koh Nakata, Hideyuki Ito, Takatomo Morita, Ikumi Matsushita, Minako Hijikata, Shinsaku Sakurada, Takehiko Sasazuki, Hidetoshi Inoko

    JOURNAL OF INFECTIOUS DISEASES　199　(11)　1707-1715　2009/06

    DOI： 10.1086/598982 　

    ISSN： 0022-1899

  131. Transcriptional dysregulation: a cause of dystonia? Peer-reviewed

    Gen Tamiya

    LANCET NEUROLOGY　8　(5)　416-418　2009/05

    DOI： 10.1016/S1474-4422(09)70087-0 　

    ISSN： 1474-4422

  132. Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice Peer-reviewed

    Kengo Tomita, Yuichi Oike, Toshiaki Teratani, Takashi Taguchi, Masaaki Noguchi, Takahiro Suzuki, Akiko Mizutani, Hirokazu Yokoyama, Rie Irie, Hidetoshi Sumimoto, Atsushi Takayanagi, Kiichi Miyashita, Masaki Akao, Mitsuhisa Tabata, Gen Tamiya, Tamiko Ohkura, Toshifumi Hibi

    HEPATOLOGY　48　(2)　458-473　2008/08

    DOI： 10.1002/hep.22365 　

    ISSN： 0270-9139

  133. Genetic analysis of craniofacial traits in the medaka Peer-reviewed

    Tetsuaki Kimura, Atsuko Shimada, Noriyoshi Sakai, Hiroshi Mitani, Kiyoshi Naruse, Hiroyuki Takeda, Hidetoshi Inoko, Gen Tamiya, Minori Shinya

    GENETICS　177　(4)　2379-2388　2007/12

    DOI： 10.1534/genetics.106.068460 　

    ISSN： 0016-6731

  134. Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity Peer-reviewed

    Kouji Maeda, Ryuji Kaji, Katsuhito Yasuno, Jamiyansuren Jambaldorj, Hiroyuki Nodera, Hiroshi Takashima, Masanori Nakagawa, Satoshi Makino, Gen Tamiya

    JOURNAL OF HUMAN GENETICS　52　(11)　907-914　2007/11

    DOI： 10.1007/s10038-007-0193-7 　

    ISSN： 1434-5161

  135. Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism Peer-reviewed

    Satoshi Makino, Ryuji Kaji, Satoshi Ando, Maiko Tomizawa, Katsuhito Yasuno, Satoshi Goto, Shinnichi Matsumoto, Ma. Daisy Tabuena, Elma Maranon, Marita Dantes, Lillian V. Lee, Kazumasa Ogasawara, Ikuo Tooyama, Hiroyasu Akatsu, Masataka Nishimura, Gen Tamiya

    AMERICAN JOURNAL OF HUMAN GENETICS　80　(3)　393-406　2007/03

    DOI： 10.1086/512129 　

    ISSN： 0002-9297

  136. Synergistic association of mitochondrial uncoupling protein (UCP) genes with schizophrenia Peer-reviewed

    Katsuhito Yasuno, Satoshi Ando, Shinnosuke Misumi, Satoshi Makino, Jerzy K. Kulski, Tatsuyuki Muratake, Naoshi Kaneko, Hideki Amagane, Toshiyuki Someya, Hidetoshi Inoko, Hidemichi Suga, Kousuke Kanemoto, Gen Tamiya

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS　144B　(2)　250-253　2007/03

    DOI： 10.1002/ajmg.b.30443 　

    ISSN： 1552-4841

  137. TAF1 as the most plausible disease gene for XDP/DYT3 [4] Peer-reviewed

    Gen Tamiya, Satoshi Makino, Ryuji Kaji

    American Journal of Human Genetics　81　(2)　417-418　2007

    Publisher: University of Chicago Press

    DOI： 10.1086/519531 　

    ISSN： 0002-9297

  138. Genomewide association analysis of human narcolepsy and a new resistance gene Peer-reviewed

    Minae Kawashima, Gen Tamiya, Akira Oka, Hirohiko Hohjoh, Takeo Juji, Takashi Ebisawa, Yutaka Honda, Hidetoshi Inoko, Katsushi Tokunaga

    AMERICAN JOURNAL OF HUMAN GENETICS　79　(2)　252-263　2006/08

    DOI： 10.1086/505539 　

    ISSN： 0002-9297

  139. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice Peer-reviewed

    K Tomita, G Tamiya, S Ando, K Ohsumi, T Chiyo, A Mizutani, N Kitamura, K Toda, T Kaneko, Y Horie, JY Han, S Kato, M Shimoda, Y Oike, M Tomizawa, S Makino, T Ohkura, H Saito, N Kumagai, H Nagata, H Ishii, T Hibi

    GUT　55　(3)　415-424　2006/03

    DOI： 10.1136/gut.2005.071118 　

    ISSN： 0017-5749

  140. Genetic linkage map of medaka with polymerase chain reaction length polymorphisms Peer-reviewed

    T Kimura, K Yoshida, A Shimada, T Jindo, M Sakaizumi, H Mitani, K Naruse, H Takeda, H Inoko, G Tamiya, M Shinya

    GENE　363　24-31　2005/12

    DOI： 10.1016/j.gene.2005.07.043 　

    ISSN： 0378-1119

  141. Gene expression profiling of Japanese psoriatic skin reveals an increased activity in molecular stress and immune response signals Peer-reviewed

    JK Kulski, W Kenworthy, M Bellgard, R Taplin, K Okamoto, A Oka, T Mabuchi, A Ozawa, G Tamiya, H Inoko

    JOURNAL OF MOLECULAR MEDICINE-JMM　83　(12)　964-975　2005/12

    DOI： 10.1007/s00109-005-0721-x 　

    ISSN： 0946-2716

  142. AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats Peer-reviewed

    K Tomita, G Tamiya, S Ando, N Kitamura, H Koizumi, S Kato, Y Horie, T Kaneko, T Azuma, H Nagata, H Ishii, T Hibi

    ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH　29　(12)　240S-245S　2005/12

    DOI： 10.1097/01.alc.0000191126.11479.69 　

    ISSN： 0145-6008

  143. Molecular dissection and anatomical basis of dystonia: X-linked recessive dystonia-parkinsonism (DYT3) Peer-reviewed

    Ryuji Kaji, Satoshi Goto, Gen Tamiya, Satoshi Ando, Satoshi Makino, L. V. Lee

    Journal of Medical Investigation　52　280-283　2005/11

    DOI： 10.2152/jmi.52.280 　

    ISSN： 1343-1420

  144. Immunohistochemical study TAFII250 in the rat laryngeal of nervous system Peer-reviewed

    H Okano, H Bamba, Y Hisa, S Makino, S Ando, G Tamiya, S Goto, R Kaji, H Kimura, Tooyama, I

    HISTOLOGY AND HISTOPATHOLOGY　20　(4)　1029-1035　2005/10

    DOI： 10.14670/HH-20.1029 　

    ISSN： 0213-3911

  145. Genetic features of Khoton Mongolians revealed by SNP analysis of the X chromosome Peer-reviewed

    T Katoh, S Mano, B Munkhbat, K Tounai, G Oyungerel, GT Chae, H Han, GJ Jia, K Tokunaga, N Munkhtuvshin, G Tamiya, H Inoko

    GENE　357　(2)　95-102　2005/09

    DOI： 10.1016/j.gene.2005.06.029 　

    ISSN： 0378-1119

  146. Whole genome association study of rheumatoid arthritis using 27 039 microsatellites Peer-reviewed

    G Tamiya, M Shinya, T Imanishi, T Ikuta, S Makino, K Okamoto, K Furugaki, T Matsumoto, S Mano, S Ando, Y Nozaki, W Yukawa, R Nakashige, D Yamaguchi, H Ishibashi, M Yonekura, Y Nakami, S Takayama, T Endo, T Saruwatari, M Yagura, Y Yoshikawa, K Fujimoto, A Oka, S Chiku, SEV Linsen, MJ Giphart, JK Kulski, T Fukazawa, H Hashimoto, M Kimura, Y Hoshina, Y Suzuki, T Hotta, J Mochida, T Minezaki, K Komai, S Shiozawa, A Taniguchi, H Yamanaka, N Kamatani, T Gojobori, S Bahram, H Inoko

    HUMAN MOLECULAR GENETICS　14　(16)　2305-2321　2005/08

    DOI： 10.1093/hmg/ddi234 　

    ISSN： 0964-6906

  147. Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism Peer-reviewed

    S Goto, LV Lee, EL Munoz, Tooyama, I, G Tamiya, S Makino, S Ando, MB Dantes, K Yamada, S Matsumoto, H Shimazu, J Kuratsu, A Hirano, R Kaji

    ANNALS OF NEUROLOGY　58　(1)　7-17　2005/07

    DOI： 10.1002/ana.20513 　

    ISSN： 0364-5134

  148. Genetic features of Mongolian ethnic groups revealed by Y-chromosomal analysis Peer-reviewed

    T Katoh, B Munkhbat, K Tounai, S Mano, H Ando, G Oyungerel, GT Chae, H Han, GJ Jia, K Tokunaga, N Munkhtuvshin, G Tamiya, H Inoko

    GENE　346　63-70　2005/02

    DOI： 10.1016/j.gene.2004.10.023 　

    ISSN： 0378-1119

  149. Identification and characterization of novel variants of the thioredoxin reductase 3 new transcript 1 TXNRD3NT1 Peer-reviewed

    Y Matsuzaka, K Okamoto, T Mabuchi, M Iizuka, A Ozawa, A Oka, G Tamiya, JK Kulski, H Inoko

    MAMMALIAN GENOME　16　(1)　41-49　2005/01

    DOI： 10.1007/s00335-004-2416-y 　

    ISSN： 0938-8990

  150. Identification, expression analysis and polymorphism of a novel RLTPR gene encoding a RGD motif, tropomodulin domain and proline/leucine-rich regions Peer-reviewed

    Y Matsuzaka, K Okamoto, T Mabuchi, M Iizuka, A Ozawa, A Oka, G Tamiya, JK Kulski, H Inoko

    GENE　343　(2)　291-304　2004/12

    DOI： 10.1016/j.gene.2004.09.004 　

    ISSN： 0378-1119

  151. Leptin deficiency enhances sensitivity of rats to alcoholic steatohepatitis through suppression of metallothionein Peer-reviewed

    K Tomita, T Azuma, N Kitamura, G Tamiya, S Ando, H Nagata, S Kato, S Inokuchi, T Nishimura, H Ishii, T Hibi

    AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY　287　(5)　G1078-G1085　2004/11

    DOI： 10.1152/ajpgi.00107.2004 　

    ISSN： 0193-1857

  152. hRDH-E2 gene polymorphisms, variable transcriptional start sites, and psoriasis Peer-reviewed

    Y Matsuzaka, K Okamoto, Y Yoshikawa, A Takaki, A Oka, T Mabuchi, M Iizuka, A Ozawa, G Tamiya, JK Kulski, H Inoko

    MAMMALIAN GENOME　15　(8)　668-675　2004/08

    DOI： 10.1007/s00335-004-2349-5 　

    ISSN： 0938-8990

  153. Integrative annotation of 21,037 human genes validated by full-length cDNA clones Peer-reviewed

    T Imanishi, T Itoh, Y Suzuki, C O'Donovan, S Fukuchi, KO Koyanagi, RA Barrero, T Tamura, Y Yamaguchi-Kabata, M Tanino, K Yura, S Miyazaki, K Ikeo, K Homma, A Kasprzyk, T Nishikawa, M Hirakawa, J Thierry-Mieg, D Thierry-Mieg, J Ashurst, LB Jia, M Nakao, MA Thomas, N Mulder, Y Karavidopoulou, LH Jin, S Kim, T Yasuda, B Lenhard, E Eveno, Y Suzuki, C Yamasaki, J Takeda, C Gough, P Hilton, Y Fujii, H Sakai, S Tanaka, C Amid, M Bellgard, MD Bonaldo, H Bono, SK Bromberg, AJ Brookes, E Bruford, P Carninci, C Chelala, C Couillault, SJ de Souza, MA Debily, MD Devignes, Dubchak, I, T Endo, A Estreicher, E Eyras, K Fukami-Kobayash, GR Gopinath, E Graudens, Y Hahn, M Han, ZG Han, K Hanada, H Hanaoka, E Harada, K Hashimoto, U Hinz, M Hirai, T Hishiki, Hopkinson, I, S Imbeaud, H Inoko, A Kanapin, Y Kaneko, T Kasukawa, J Kelso, P Kersey, R Kikuno, K Kimura, B Korn, Kuryshev, V, Makalowska, I, T Makino, S Mano, R Mariage-Samson, J Mashima, H Matsuda, HW Mewes, S Minoshima, K Nagai, H Nagasaki, N Nagata, R Nigam, O Ogasawara, O Ohara, M Ohtsubo, N Okada, T Okido, S Oota, M Ota, T Ota, T Otsuki, D Piatier-Tonneau, A Poustka, SX Ren, N Saitou, K Sakai, S Sakamoto, R Sakate, Schupp, I, F Servant, S Sherry, R Shiba, N Shimizu, M Shimoyama, AJ Simpson, B Soares, C Steward, M Suwa, M Suzuki, A Takahashi, G Tamiya, H Tanaka, T Taylor, JD Terwilliger, P Unneberg, Veeramachaneni, V, S Watanabe, L Wilming, N Yasuda, HS Yoo, M Stodolsky, W Makalowski, M Go, K Nakai, T Takagi, M Kanehisa, Y Sakaki, J Quackenbush, Y Okazaki, Y Hayashizaki, W Hide, R Chakraborty, K Nishikawa, H Sugawara, Y Tateno, Z Chen, M Oishi, P Tonellato, R Apweiler, K Okubo, L Wagner, S Wiemann, RL Strausberg, T Isogai, C Auffray, N Nomura, T Gojobori, S Sugano

    PLOS BIOLOGY　2　(6)　856-875　2004/06

    DOI： 10.1371/journal.pbio.0020162 　

    ISSN： 1545-7885

  154. Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world Peer-reviewed

    T Nakajima, S Wooding, T Sakagami, M Emi, K Tokunaga, G Tamiya, T Ishigami, S Umemura, B Munkhbat, F Jin, J Guan-jun, Hayasaka, I, T Ishida, N Saitou, K Pavelka, JM Lalouel, LB Jorde, Inoue, I

    AMERICAN JOURNAL OF HUMAN GENETICS　74　(5)　898-916　2004/05

    DOI： 10.1086/420793 　

    ISSN： 0002-9297

  155. Notes on the maximum likelihood estimation of haplotype frequencies Peer-reviewed

    S Mano, N Yasuda, T Katoh, K Tounai, H Inoko, T Imanishi, G Tamiya, T Gojobori

    ANNALS OF HUMAN GENETICS　68　(Pt 3)　257-264　2004/05

    DOI： 10.1046/j.1529-8817.2003.00088.x 　

    ISSN： 0003-4800

  156. Identification of two new C4 alleles by DNA sequencing and evidence for a historical recombination of serologically defined C4A and C4B alleles Peer-reviewed

    J Hui, A Oka, M Tomizawa, GK Tay, JK Kulski, WJ Penhale, SPA Iaschi, S Makino, G Tamiya, H Inoko

    TISSUE ANTIGENS　63　(3)　263-269　2004/03

    DOI： 10.1111/j.1399-0039.2004.0175.x 　

    ISSN： 0001-2815

  157. Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met Peer-reviewed

    K Tomita, T Azuma, N Kitamura, J Nishida, G Tamiya, A Oka, S Inokuchi, T Nishimura, M Suematsu, H Ishii

    GASTROENTEROLOGY　126　(3)　873-885　2004/03

    DOI： 10.1053/j.gastro.2003.12.008 　

    ISSN： 0016-5085

  158. Novel algorithm for automated genotyping of microsatellites Peer-reviewed

    T Matsumoto, W Yukawa, Y Nozaki, R Nakashige, M Shinya, S Makino, M Yagura, T Ikuta, T Imanishi, H Inoko, G Tamiya, T Gojobori

    NUCLEIC ACIDS RESEARCH　32　(20)　6069-6077　2004

    DOI： 10.1093/nar/gkh946 　

    ISSN： 0305-1048

  159. Identification of NAD(+)-dependent isocitrate dehydrogenase 3 gamma-like (IDH3GL) gene and its genetic polymorphisms Peer-reviewed

    K Okamoto, Y Matsuzaka, Y Yoshikawa, A Takaki, JK Kulski, G Tamiya, H Inoko

    GENE　323　141-148　2003/12

    DOI： 10.1016/j.gene.2003.09.014 　

    ISSN： 0378-1119

  160. Toward identification of susceptibility genes for sporadic Parkinson's disease Peer-reviewed

    T Toda, Y Momose, M Murata, G Tamiya, M Yamamoto, N Hattori, H Inoko

    JOURNAL OF NEUROLOGY　250　40-43　2003/10

    DOI： 10.1007/s00415-003-1307-6 　

    ISSN： 0340-5354

  161. Corneodesmosin gene: no evidence for PSORS 1 gene in North-eastern Thai psoriasis patients Peer-reviewed

    AV Romphruk, A Oka, A Romphruk, M Tomizawa, C Choonhakarn, TK Naruse, C Puapairoj, G Tamiya, C Leelayuwat, H Inoko

    TISSUE ANTIGENS　62　(3)　217-224　2003/09

    DOI： 10.1034/j.1399-0039.2003.00056.x 　

    ISSN： 0001-2815

  162. Localization of a non-melanoma skin cancer susceptibility region within the major histocompatibility complex by association analysis using microsatellite markers Peer-reviewed

    A Oka, H Hayashi, M Tomizawa, K Okamoto, L Suyun, J Hui, JK Kulski, J Beilby, G Tamiya, H Inoko

    TISSUE ANTIGENS　61　(3)　203-210　2003/03

    DOI： 10.1034/j.1399-0039.2003.00007.x 　

    ISSN： 0001-2815

  163. Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis Peer-reviewed

    K Okamoto, S Makino, Y Yoshikawa, A Takaki, Y Nagatsuka, M Ota, G Tamiya, A Kimura, S Bahram, H Inoko

    AMERICAN JOURNAL OF HUMAN GENETICS　72　(2)　303-312　2003/02

    DOI： 10.1086/346067 　

    ISSN： 0002-9297

  164. SLURP-2, a novel member of the human Ly-6 superfamily that is up-regulated in psoriasis vulgaris Peer-reviewed

    H Tsuji, K Okamoto, Y Matsuzaka, H Iizuka, G Tamiya, H Inoko

    GENOMICS　81　(1)　26-33　2003/01

    DOI： 10.1016/S0888-7543(02)00025-3 　

    ISSN： 0888-7543

  165. Identification of the hRDH-E2 gene, a novel member of the SDR family, and its increased expression in psoriatic lesion Peer-reviewed

    Y Matsuzaka, K Okamoto, H Tsuji, T Mabuchi, A Ozawa, G Tamiya, H Inoko

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　297　(5)　1171-1180　2002/10

    DOI： 10.1016/S0006-291X(02)02344-6 　

    ISSN： 0006-291X

  166. Genetic isolates in East Asia: A study of linkage disequilibrium in the X chromosome Peer-reviewed

    T Katoh, S Mano, T Ikuta, B Munkhbat, K Tounai, H Ando, N Munkhtuvshin, T Imanishi, H Inoko, G Tamiya

    AMERICAN JOURNAL OF HUMAN GENETICS　71　(2)　395-400　2002/08

    DOI： 10.1086/341608 　

    ISSN： 0002-9297

  167. Identification of novel candidate genes in the diffuse panbronchiolitis critical region of the class I human MHC Peer-reviewed

    Y Matsuzaka, K Tounai, A Denda, M Tomizawa, S Makino, K Okamoto, N Keicho, A Oka, JK Kulski, G Tamiya, H Inoko

    IMMUNOGENETICS　54　(5)　301-309　2002/08

    DOI： 10.1007/s00251-002-0470-8 　

    ISSN： 0093-7711

  168. Susceptibility locus for non-obstructive azoospermia is localized within the HLA-DR/DQ subregion: Primary role of DQB1*0604 Peer-reviewed

    Y Matsuzaka, S Makino, K Okamoto, A Oka, A Tsujimura, K Matsumiya, S Takahara, A Okuyama, M Sada, R Gotoh, T Nakatani, M Ota, Y Katsuyama, G Tamiya, H Inoko

    TISSUE ANTIGENS　60　(1)　53-63　2002/07

    DOI： 10.1034/j.1399-0039.2002.600107.x 　

    ISSN： 0001-2815

  169. Corneodesmosin DNA polymorphisms in MHC haplotypes and Japanese patients with psoriasis Peer-reviewed

    J Hui, A Oka, G Tamiya, M Tomizawa, JK Kulski, WJ Penhale, GK Tay, M Iizuka, A Ozawa, H Inoko

    TISSUE ANTIGENS　60　(1)　77-83　2002/07

    DOI： 10.1034/j.1399-0039.2002.600110.x 　

    ISSN： 0001-2815

  170. Association of a determinant on mouse chromosome 18 with experimental severe Plasmodium berghei malaria Peer-reviewed

    E Nagayasu, K Nagakura, M Akaki, G Tamiya, S Makino, Y Nakano, M Kimura, M Aikawa

    INFECTION AND IMMUNITY　70　(2)　512-516　2002/02

    DOI： 10.1128/IAI.70.2.512-516.2002 　

    ISSN： 0019-9567

  171. Genomic anatomy of a premier major histocompatibility complex paralogous region on chromosome 1q21-q22 Peer-reviewed

    T Shiina, A Ando, Y Suto, F Kasai, A Shigenari, N Takishima, E Kikkawa, K Iwata, Y Kuwano, Y Kitamura, Y Matsuzawa, K Sano, M Nogami, H Kawata, SY Li, Y Fukuzumi, M Yamazaki, H Tashiro, G Tamiya, A Kohda, K Okumura, T Ikemura, E Soeda, N Mizuki, M Kimura, S Bahram, H Inoko

    GENOME RESEARCH　11　(5)　789-802　2001/05

    DOI： 10.1101/gr.175801 　

    ISSN： 1088-9051

  172. New polymorphic microsatellite markers in the human MHC class III region Peer-reviewed

    Y Matsuzaka, S Makino, K Nakajima, M Tomizawa, A Oka, S Bahram, JK Kulski, G Tamiya, H Inoko

    TISSUE ANTIGENS　57　(5)　397-404　2001/05

    DOI： 10.1034/j.1399-0039.2001.057005397.x 　

    ISSN： 0001-2815

  173. Bioinformatics issues for automating the annotation of genomic sequences. Peer-reviewed

    Carter K, Oka A, Tamiya G, Bellgard MI

    Genome Inform Ser　12　204-11　2001

    DOI： 10.11234/gi1990.12.204 　

  174. New polymorphic microsatellite markers in the human MHC class II region Peer-reviewed

    Y Matsuzaka, S Makino, K Nakajima, M Kimura, S Bahram, G Tamiya, H Inoko

    TISSUE ANTIGENS　56　(6)　492-500　2000/12

    DOI： 10.1034/j.1399-0039.2000.560602.x 　

    ISSN： 0001-2815

  175. Genomic organization, chromosomal localization, and the complete 22 kb DNA sequence of the human GCMa/GCM1, a placenta-specific transcription factor gene Peer-reviewed

    K Yamada, H Ogawa, G Tamiya, M Ikeno, M Morita, S Asakawa, N Shimizu, T Okazaki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　278　(1)　134-139　2000/11

    DOI： 10.1006/bbrc.2000.3775 　

    ISSN： 0006-291X

  176. Gene structure and promoter for Crad2 encoding mouse cis-retinol/3 alpha-hydroxysterol short-chain dehydrogenase isozyme Peer-reviewed

    K Tomita, M Sato, K Kajiwara, M Tanaka, G Tamiya, S Makino, M Tomizawa, A Mizutani, Y Kuwano, T Shiina, H Ishii, M Kimura

    GENE　251　(2)　175-186　2000/06

    DOI： 10.1016/S0378-1119(00)00194-3 　

    ISSN： 0378-1119

  177. Fine localization of a major disease-susceptibility locus for diffuse panbronchiolitis Peer-reviewed

    N Keicho, J Ohashi, G Tamiya, K Nakata, Y Taguchi, A Azuma, N Ohishi, M Emi, MH Park, H Inoko, K Tokunaga, S Kudoh

    AMERICAN JOURNAL OF HUMAN GENETICS　66　(2)　501-507　2000/02

    DOI： 10.1086/302786 　

    ISSN： 0002-9297

  178. Molecular dynamics of MHC genesis unraveled by sequence analysis of the 1,796,938-bp HLA class I region Peer-reviewed

    T Shiina, G Tamiya, A Oka, N Takishima, T Yamagata, E Kikkawa, K Iwata, M Tomizawa, N Okuaki, Y Kuwano, K Watanabe, Y Fukuzumi, S Itakura, C Sugawara, A Ono, M Yamazaki, H Tashiro, A Ando, T Ikemura, E Soeda, M Kimura, S Bahram, H Inoko

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　96　(23)　13282-13287　1999/11

    DOI： 10.1073/pnas.96.23.13282 　

    ISSN： 0027-8424

  179. Association analysis using refined microsatellite markers localizes a susceptibility locus for psoriasis vulgaris within a 111 kb segment telomeric to the HLA-C gene Peer-reviewed

    A Oka, G Tamiya, M Tomizawa, M Ota, Y Katsuyama, S Makino, T Shiina, M Yoshitome, M Iizuka, Y Sasao, K Iwashita, Y Kawakubo, J Sugai, A Ozawa, M Ohkido, M Kimura, S Bahram, H Inoko

    HUMAN MOLECULAR GENETICS　8　(12)　2165-2170　1999/11

    DOI： 10.1093/hmg/8.12.2165 　

    ISSN： 0964-6906

  180. Complete sequence and gene map of a human major histocompatibility complex Peer-reviewed

    S Beck, D Geraghty, H Inoko, L Rowen, B Aguado, S Bahram, RD Campbell, SA Forbes, T Guillaudeux, L Hood, R Horton, M Janer, C Jasoni, A Madan, S Milne, M Neville, A Oka, S Qin, G Ribas-Despuig, J Rogers, T Shiina, T Spies, G Tamiya, H Tashiro, J Trowsdale, Q Vu, L Williams, M Yamazaki

    NATURE　401　(6756)　921-923　1999/10

    DOI： 10.1038/44853 　

    ISSN： 0028-0836

  181. New polymorphic microsatellite markers in the human MHC class I region Peer-reviewed

    G Tamiya, T Shiina, A Oka, M Tomizawa, M Ota, Y Katsuyama, M Yoshitome, S Makino, M Kimura, H Inoko

    TISSUE ANTIGENS　54　(3)　221-228　1999/09

    DOI： 10.1034/j.1399-0039.1999.540302.x 　

    ISSN： 0001-2815

  182. The critical region for Behcet disease in the human major histocompatibility complex is reduced to a 46-kb segment centromeric of HLA-B, by association analysis using refined microsatellite mapping Peer-reviewed

    M Ota, N Mizuki, Y Katsuyama, G Tamiya, T Shiina, A Oka, H Ando, M Kimura, K Goto, S Ohno, H Inoko

    AMERICAN JOURNAL OF HUMAN GENETICS　64　(5)　1406-1410　1999/05

    DOI： 10.1086/302364 　

    ISSN： 0002-9297

  183. Genome sequencing analysis of the 1.8 Mb entire human MHC class I region Peer-reviewed

    T Shiina, G Tamiya, A Oka, N Takishima, H Inoko

    IMMUNOLOGICAL REVIEWS　167　193-199　1999/02

    DOI： 10.1111/j.1600-065X.1999.tb01392.x 　

    ISSN： 0105-2896

  184. Physical mapping between the S and HLA-E genes in the human MHC class I region: construction of a BAC, PAC, and cosmid contig Peer-reviewed

    T Shiina, E Kikkawa, W Saito, G Tamiya, A Oka, K Watanabe, M Yamazaki, H Tashiro, K Okumura, A Ando, M Kimura, E Soeda, P Pontarotti, H Inoko

    IMMUNOGENETICS　48　(6)　402-407　1998/11

    DOI： 10.1007/s002510050451 　

    ISSN： 0093-7711

  185. Microsatellite polymorphism within the MICB gene among Japanese patients with Behcet's disease Peer-reviewed

    T Kimura, K Goto, K Yabuki, N Mizuki, G Tamiya, M Sato, M Kimura, H Inoko, S Ohno

    HUMAN IMMUNOLOGY　59　(8)　500-502　1998/08

    DOI： 10.1016/S0198-8859(98)00047-0 　

    ISSN： 0198-8859

  186. Twenty-six new polymorphic microsatellite markers around the HLA-B, -C and -E loci in the human MHC class I region Peer-reviewed

    G Tamiya, M Ota, Y Katsuyama, T Shiina, A Oka, S Makino, M Kimura, H Inoko

    TISSUE ANTIGENS　51　(4)　337-346　1998/04

    ISSN： 0001-2815

  187. Nucleotide sequencing analysis of the 146-kilobase segment around the IkBL and MICA genes at the centromeric end of the HLA class I region Peer-reviewed

    T Shiina, G Tamiya, A Oka, T Yamagata, N Yamagata, E Kikkawa, K Goto, N Mizuki, K Watanabe, Y Fukuzumi, S Taguchi, C Sugawara, A Ono, L Chen, M Yamazaki, H Tashiro, A Ando, T Ikemura, M Kimura, H Inoko

    GENOMICS　47　(3)　372-382　1998/02

    DOI： 10.1006/geno.1997.5114 　

    ISSN： 0888-7543

  188. An embryological study of ventralization of dorsal structures in the tail of medaka (Oryzias latipes) Da mutants Peer-reviewed

    G Tamiya, Y Wakamatsu, K Ozato

    DEVELOPMENT GROWTH & DIFFERENTIATION　39　(4)　531-538　1997/08

    DOI： 10.1046/j.1440-169X.1997.t01-1-00015.x 　

    ISSN： 0012-1592

  189. Physical mapping 220 kb centromeric of the human MHC and DNA sequence analysis of the 43-kb segment including the RING1, HKE6, and HKE4 genes Peer-reviewed

    YY Kikuti, G Tamiya, A Ando, L Chen, M Kimura, E Ferreira, K Tsuji, J Trowsdale, H Inoko

    GENOMICS　42　(3)　422-435　1997/06

    DOI： 10.1006/geno.1997.4745 　

    ISSN： 0888-7543

  190. Genomic structure of the human MHC class I MICB gene Peer-reviewed

    S Bahram, T Shiina, A Oka, G Tamiya, H Inoko

    IMMUNOGENETICS　45　(2)　161-162　1996

    DOI： 10.1007/s002510050184 　

    ISSN： 0093-7711

  191. An efficient expression vector for transgenic medaka construction. Peer-reviewed

    Takagi S, Sasado T, Tamiya G, Ozato K, Wakamatsu Y, Takeshita A, Kimura M

    Mol Mar Biol Biotechnol (Mar Biotechnol)　3　(4)　192-9　1994

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Misc. 6

  1. 大規模ゲノム配列決定時代の遺伝統計学

    田宮 元

    実験医学増刊　41　(7)　18-23　2023/04

  2. 医療全般におけるDXの現状

    仁宮洸太, 高山 順, 田宮 元

    肝胆膵　86　(2)　129-138　2023/02

  3. 東北メディカル・メガバンク機構のGWAS要約統計量データベース

    成田 暁, 田宮 元

    遺伝子医学　12　(1)　16-19　2022/01

  4. 生活習慣病とゲノムワイド関連解析

    田宮 元

    医学のあゆみ　278　(5)　347-352　2021/07

  5. 統計的機械学習によるゲノムリスク予測

    TAMIYA Gen, UEKI Masao

    Precision Medicine　2　(12)　23-26　2019/11

  6. バイオバンク・ゲノムコホートデータの人工知能解析

    TAMIYA Gen

    実験医学　37　(16)　2712-2713　2019/10

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Books and Other Publications 5

  1. 全ゲノム・エクソーム遺伝統計解析 : Python, Rで実践して身につく, 未知の遺伝要因の探索と疾患リスク予測

    田宮, 元

    羊土社　2023/09

    ISBN: 9784758122665

  2. 新版医学統計学ハンドブック

    植木優夫, 田宮 元

    朝倉書店　2018/07

    ISBN: 4254122292

  3. 遺伝統計学と疾患ゲノムデータ解析–病態解明から個別化医療,ゲノム創薬まで–

    植木優夫, 田宮 元

    メディカルドゥ　2018/04

    ISBN: 4944157630

  4. ゲノム医学のための遺伝統計学

    田宮 元, 植木 優夫, 小森 理

    共立出版　2015/03

    ISBN: 9784320111172

  5. 予防医学辞典

    田宮 元

    朝倉書店　2005/05

    ISBN: 4254300816

Research Projects 5

  1. マルチスケール精神病データの疎性モデリング解析 Competitive

    TAMIYA Gen

    Offer Organization: 文部科学省

    System: 科学研究費補助金新学術領域研究(研究領域提案型)

    2019/04 - 2021/03

  2. 深層学習による大規模ゲノムコホート解析 Competitive

    TAMIYA Gen

    Offer Organization: 日本学術振興会

    System: 科学研究費補助金基盤研究(C)

    2016/04 - 2019/03

  3. スパースモデリングによる大規模ゲノムコホート解析 Competitive

    TAMIYA Gen

    Offer Organization: 文部科学省

    System: 科学研究費補助金新学術領域研究(研究領域提案型)

    2016/04 - 2018/03

  4. ゲノムコホート研究のための遺伝統計学 Competitive

    TAMIYA Gen

    Offer Organization: 日本学術振興会

    System: 科学研究費補助金基盤研究(C)

    2013/04 - 2016/03

  5. パーソナルゲノム情報のための遺伝統計手法の開発 Competitive

    TAMIYA Gen

    Offer Organization: 文部科学省

    System: 科学研究費補助金新学術領域研究(研究領域提案型)

    2013/04 - 2015/03