東北大学研究者紹介

研究者詳細

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日本語 English

顔写真

タミヤ　ゲン

田宮　元

Gen Tamiya

所属

大学院医学系研究科　創生応用医学研究センター　ＡＩフロンティア新医療創生分野

職名

教授

学位

博士（理学）（名古屋大学）
修士（人間・環境学）（京都大学）

researchmap

https://researchmap.jp/read0082102

J-GLOBAL ID

200901063773876525

委員歴 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年12月～継続中
日本メディカルAI学会　理事

2018年1月～継続中

所属学協会 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

研究キーワード 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

研究分野 4

情報通信 / 知能情報学 /
情報通信 / 統計科学 /
ライフサイエンス / 医化学 /
ライフサイエンス / 遺伝学 /

論文 191

Translational genomics of osteoarthritis in 1,962,069 individuals 査読有り

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年4月9日
出版者・発行元： 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.
Profiling of runs of homozygosity from whole-genome sequence data in Japanese biobank 査読有り

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年4月3日
出版者・発行元： 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.
Sex difference in genetic risk in the prevalence of atrial fibrillation 査読有り

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年3月23日
出版者・発行元： Elsevier BV
DOI： 10.1016/j.hrthm.2025.03.1974 　

ISSN：1547-5271
Genetic effects on gestational diabetes mellitus and their interactions with environmental factors among Japanese women 査読有り

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年3月21日
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s10038-025-01330-4 　

ISSN：1434-5161

eISSN：1435-232X
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年12月1日
出版者・発行元： Japan Atherosclerosis Society
DOI： 10.5551/jat.64906 　

ISSN：1340-3478

eISSN：1880-3873
Metabolomic Profiling of Open-Angle Glaucoma Etiologic Endotypes: Tohoku Multi-Omics Glaucoma Study 査読有り

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年11月20日
出版者・発行元： Association for Research in Vision and Ophthalmology (ARVO)
DOI： 10.1167/iovs.65.13.44 　

ISSN：1552-5783
Early prediction of hypertensive disorders of pregnancy toward preventive early intervention 査読有り

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年11月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.xagr.2024.100383 　

ISSN：2666-5778
Next-generation sequencing analysis with a population-specific human reference genome 査読有り

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年10月28日
出版者・発行元： Genetics Society of Japan
DOI： 10.1266/ggs.24-00112 　

ISSN：1341-7568

eISSN：1880-5779
A Prevalent TMEM260 Deletion Causes Conotruncal Heart Defects, Including Truncus Arteriosus 査読有り

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年10月19日
出版者・発行元： 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.
Inconsistent embryo selection across polygenic score methods 査読有り

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年10月14日
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s41562-024-02019-y 　

eISSN：2397-3374
Comprehensive genetic analysis for identification of monogenic disorders and selection of appropriate treatments in pediatric patients with persistent thrombocytopenia 査読有り

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年9月24日
出版者・発行元： Informa UK Limited
DOI： 10.1080/08880018.2024.2395358 　

ISSN：0888-0018

eISSN：1521-0669
Identification of risk loci for postpartum depression in a genome‐wide association study 査読有り

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年9月17日
出版者・発行元： 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.
Idiopathic infantile hypercalcemia with a CYP24A1 variant triggered by vitamin D supplementation in fortified milk: A case report 査読有り

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年9月9日
出版者・発行元： Japanese Society for Pediatric Endocrinology
DOI： 10.1297/cpe.2024-0049 　

ISSN：0918-5739

eISSN：1347-7358
Genome-wide association study based on clustering by obesity-related variables uncovers a genetic architecture of obesity in the Japanese and the UK populations 査読有り

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年8月30日
出版者・発行元： Elsevier BV
DOI： 10.1016/j.heliyon.2024.e36023 　

ISSN：2405-8440
Machine learning-based reproducible prediction of type 2 diabetes subtypes 査読有り

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年8月21日
出版者・発行元： 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 (T2D_kmeans) by unsupervised k-means clustering based on Ahlqvist’s variables (age at diagnosis, BMI, HbA_1c, 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 (T2D_RF15). 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 T2D_RF15 demonstrated a 94% accuracy for predicting T2D_kmeans 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%). T2D_RF15 showed an accuracy of 82.9% for detecting T2D_kmeans, also in a putative subset with missing insulin-related variables, when used with an imputation algorithm. In Kaplan–Meier analysis, the diabetes clusters of T2D_RF15 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 T2D_kmeans. The predictive accuracy was improved after excluding individuals with low predictive probability, who were categorised as an ‘undecidable’ cluster. T2D_RF15, after excluding undecidable individuals, showed higher consistency (100% for SIDD, 68.6% for SIRD, 94.4% for MOD and 97.9% for MARD) than T2D_kmeans. 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
Genetic Risk Stratification of Primary Open-Angle Glaucoma in Japanese Individuals 査読有り

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年7月17日
出版者・発行元： Elsevier BV
DOI： 10.1016/j.ophtha.2024.05.026 　

ISSN：0161-6420
Associations of combined genetic and lifestyle risks with hypertension and home hypertension 査読有り

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年6月24日
出版者・発行元： 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.
Body mass index stratification optimizes polygenic prediction of type 2 diabetes in cross-biobank analyses 査読有り

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年6月11日
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s41588-024-01782-y 　

ISSN：1061-4036

eISSN：1546-1718
Long‐term clinical observation of patients with heterozygous KIF1A variants 査読有り

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年5月17日
出版者・発行元： 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.
A fine-scale genetic map of the Japanese population. 国際誌査読有り

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年5月8日

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.
Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities. 国際誌査読有り

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年5月7日

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.
Risk Factors, Prognosis, Influence on the Offspring, and Genetic Architecture of Perinatal Depression Classified Based on the Depressive Symptom Trajectory 査読有り

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年3月15日
出版者・発行元： 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.
Development of phenotyping algorithms for hypertensive disorders of pregnancy (HDP) and their application in more than 22,000 pregnant women. 国際誌査読有り

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年3月15日

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.
Genetic etiology of truncus arteriosus excluding 22q11.2 deletion syndrome and identification of c.1617del, a prevalent variant in TMEM260, in the Japanese population. 国際誌査読有り

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年2月13日

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.
Treatment of ZC4H2 Variant-Associated Spastic Paraplegia with Selective Dorsal Rhizotomy and Intensive Postoperative Rehabilitation: A Case Report. 査読有り

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年1月25日

DOI： 10.1620/tjem.2024.J004 　
Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS). 査読有り

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年1月6日

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.
Evaluation of AI-assisted colposcopy for detecting high-risk subtypes of human papillomavirus in CIN2 査読有り

European Journal of Gynaecological Oncology　45　(1)　143-143　2024年
出版者・発行元： MRE Press
DOI： 10.22514/ejgo.2024.020 　

ISSN：0392-2936
Case Report: Identification of a CARD8 variant in all three patients with PFAPA syndrome complicated with Kawasaki disease. 国際誌査読有り

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年

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.
Machine Learning of Histopathological Images Predicts Recurrences of Resected Pancreatic Ductal Adenocarcinoma With Adjuvant Treatment 査読有り

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年12月21日
出版者・発行元： 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.
jMorp: Japanese Multi-Omics Reference Panel update report 2023. 国際誌査読有り

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年11月1日

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.
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. 査読有り

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年10月6日

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.
A Case Series of Patients With MYBPC1 Gene Variants Featuring Undulating Tongue Movements as Myogenic Tremor 査読有り

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年9月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.pediatrneurol.2023.06.002 　

ISSN：0887-8994
Establishment of the early prediction models of low-birth-weight reveals influential genetic and environmental factors: a prospective cohort study. 国際誌査読有り

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年8月31日

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.
Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder. 国際誌査読有り

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年5月30日

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.
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. 国際誌査読有り

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年

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.
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. 国際誌査読有り

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年12月27日

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.
Familial Paget’s disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27) 査読有り

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年12月15日
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1007/s00774-022-01392-w 　

ISSN：0914-8779

eISSN：1435-5604
Genome-wide association study of the risk of chronic kidney disease and kidney-related traits in the Japanese population: J-Kidney-Biobank. 国際誌査読有り

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年11月21日

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.
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. 国際誌査読有り

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年9月28日

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.
Construction of a trio-based structural variation panel utilizing activated T lymphocytes and long-read sequencing technology. 国際誌査読有り

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年9月20日

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.
A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids 査読有り

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年8月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.ajhg.2022.06.012 　

ISSN：0002-9297
Two Siblings with Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome 4 and a Novel Variant of ATP8A2. 査読有り

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年4月29日

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.
The longest reported sibling survivors of a severe form of congenital myasthenic syndrome with the ALG14 pathogenic variant. 国際誌査読有り

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年4月

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.
Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct. 国際誌査読有り

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年1月28日

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.
Development of a prognostic prediction support system for cervical intraepithelial neoplasia using artificial intelligence-based diagnosis 査読有り

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年

DOI： 10.3802/jgo.2022.33.e57 　
The power of genetic diversity in genome-wide association studies of lipids 査読有り

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年12月23日
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s41586-021-04064-3 　

ISSN：0028-0836

eISSN：1476-4687
dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project 査読有り

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年12月
出版者・発行元： 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.
A cross-population atlas of genetic associations for 220 human phenotypes 査読有り

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年10月
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s41588-021-00931-x 　

ISSN：1061-4036

eISSN：1546-1718
Smooth-threshold multivariate genetic prediction incorporating gene–environment interactions 査読有り

Masao Ueki, Gen Tamiya

G3 Genes|Genomes|Genetics　2021年8月6日
出版者・発行元： 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).
A patient with early-onset SMAX3 and a novel variant of ATP7A 査読有り

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年8月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.braindev.2021.08.004 　

ISSN：0387-7604
Identification and Validation of Combination Plasma Biomarker of Afamin, Fibronectin and Sex Hormone-Binding Globulin to Predict Pre-eclampsia 査読有り

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年6月1日
出版者・発行元： 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.
Japonica Array NEO with increased genome-wide coverage and abundant disease risk SNPs 査読有り

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年5月13日
出版者・発行元： 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 &gt;2.5–5% were &gt;0.9 and &gt;0.8, respectively, and &gt;12 million markers were imputed with an INFO score &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.
GWAS Identified IL4R and the Major Histocompatibility Complex Region as the Associated Loci of Total Serum IgE Levels in 9,260 Japanese Individuals 査読有り

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年4月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.jid.2021.02.762 　

ISSN：0022-202X
Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk 国際誌査読有り

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年3月
出版者・発行元： 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.
Body mass index and colorectal cancer risk: A Mendelian randomization study 国際誌査読有り

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年2月25日
出版者・発行元： 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.
ALOX12 mutation in a family with dominantly inherited bleeding diathesis 査読有り

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年2月10日
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s10038-020-00887-6 　

ISSN：1434-5161

eISSN：1435-232X
Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries 査読有り

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年2月
出版者・発行元： 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.
Heart Rate Information-Based Machine Learning Prediction of Emotions Among Pregnant Women. 国際誌査読有り

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年

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.
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 国際誌査読有り

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年1月
出版者・発行元： 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.
Facial UV photo imaging for skin pigmentation assessment using conditional generative adversarial networks 査読有り

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

Scientific Reports　11　(1)　1213　2021年1月
出版者・発行元： 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.
Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference 国際誌査読有り

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年1月
出版者・発行元： 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 > 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.
Artificial intelligence powered statistical genetics in biobanks 国際誌査読有り

Akira Narita, Masao Ueki, Gen Tamiya

Journal of Human Genetics　66　(1)　61-65　2021年1月
出版者・発行元： 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.
Identification of critical genetic variants associated with metabolic phenotypes of the Japanese population 査読有り

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年12月
出版者・発行元： 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.
Machine learning to reveal hidden risk combinations for the trajectory of posttraumatic stress disorder symptoms 査読有り

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年12月
出版者・発行元： 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.
Machine learning for effectively avoiding overfitting is a crucial strategy for the genetic prediction of polygenic psychiatric phenotypes 査読有り

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年12月
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s41398-020-00957-5 　

eISSN：2158-3188
Clustering by phenotype and genome-wide association study in autism 査読有り

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年12月
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s41398-020-00951-x 　

eISSN：2158-3188
Improved metabolomic data-based prediction of depressive symptoms using nonlinear machine learning with feature selection 査読有り

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年12月
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s41398-020-0831-9 　

eISSN：2158-3188
jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population 国際誌査読有り

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年11月12日
出版者・発行元： 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.
A genotype imputation method for de-identified haplotype reference information by using recurrent neural network 国際誌査読有り

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

PLOS Computational Biology　16　(10)　e1008207-e1008207　2020年10月1日
出版者・発行元： 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.
Maternal Baseline Characteristics and Perinatal Outcomes: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study 査読有り

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年10月
出版者・発行元： 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.
Endogenization and excision of human herpesvirus 6 in human genomes. 国際誌査読有り

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年8月
出版者・発行元： 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.
Genome-wide association study identifies new loci for albuminuria in the Japanese population. 査読有り

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年8月
出版者・発行元： 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.
Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): rationale, progress and perspective. 国際誌査読有り

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年2月1日

DOI： 10.1093/ije/dyz169 　
Study profile of The Tohoku Medical Megabank Community-Based Cohort Study. 査読有り

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年1月11日

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.
Design and Progress of Oral Health Examinations in the Tohoku Medical Megabank Project 査読有り

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年
出版者・発行元： Tohoku University Medical Press
DOI： 10.1620/tjem.251.97 　

ISSN：0040-8727

eISSN：1349-3329
Automated acquisition of explainable knowledge from unannotated histopathology images. 国際誌査読有り

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年12月18日

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.
Illuminating Clues of Cancer Buried in Prostate MR Image: Deep Learning and Expert Approaches. 国際誌査読有り

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年10月30日

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.
GWAS with principal component analysis identifies a gene comprehensively controlling rice architecture. 国際誌査読有り

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年10月

DOI： 10.1073/pnas.1904964116 　
Establishment of Integrated Biobank for Precision Medicine and Personalized Healthcare: The Tohoku Medical Megabank Project. 査読有り

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年9月

DOI： 10.31662/jmaj.2019-0014 　
In Vivo Expression of NUP93 and Its Alteration by NUP93 Mutations Causing Focal Segmental Glomerulosclerosis. 国際誌査読有り

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年9月

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.
Outlier detection for questionnaire data in biobanks. 査読有り

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年8月
出版者・発行元：
DOI： 10.1093/ije/dyz012 　

ISSN：0300-5771

eISSN：1464-3685
Quick assessment for systematic test statistic inflation/deflation due to null model misspecifications in genome-wide environment interaction studies. 査読有り

Ueki M, Fujii M, Tamiya G

PLoS ONE　14　(7)　e0219825　2019年7月

DOI： 10.1371/journal.pone.0219825 　
Susceptibility Loci for Tanning Ability in the Japanese Population Identified by a Genome-Wide Association Study from the Tohoku Medical Megabank Project Cohort Study. 査読有り

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年7月

DOI： 10.1016/j.jid.2019.01.015 　

ISSN：0022-202X

eISSN：1523-1747
Respiratory resistance among adults in a population-based cohort study in Northern Japan. 国際誌査読有り

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年5月

DOI： 10.1016/j.resinv.2018.12.008 　
Growth impairment in individuals with citrin deficiency. 国際誌査読有り

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年5月

DOI： 10.1002/jimd.12051 　
The prevalence of GALM mutations that cause galactosemia: A database of functionally evaluated variants. 国際誌査読有り

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

Mol Genet Metab　126　(4)　362-367　2019年4月

DOI： 10.1016/j.ymgme.2019.01.018 　
Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. 査読有り

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年4月
Genome analyses for the Tohoku Medical Megabank Project towards establishment of personalized healthcare. 国際誌査読有り

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年2月1日

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.
3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. 国際誌査読有り

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年

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.
Potential identification of vitamin B6 responsiveness in autism spectrum disorder utilizing phenotype variables and machine learning methods. 国際誌査読有り

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年10月4日

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.
Regional genetic differences among Japanese populations and performance of genotype imputation using whole-genome reference panel of the Tohoku Medical Megabank Project. 国際誌査読有り

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年7月24日

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.
Ethylene-gibberellin signaling underlies adaptation of rice to periodic flooding 査読有り

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年7月13日
出版者・発行元： American Association for the Advancement of Science (AAAS)
DOI： 10.1126/science.aat1577 　

ISSN：0036-8075

eISSN：1095-9203
Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. 国際誌査読有り

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年6月

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.
Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. 国際誌査読有り

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年2月

DOI： 10.1038/s10038-017-0347-1 　

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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.
Female Japanese quail visually differentiate testosterone-dependent male attractiveness for mating preferences. 査読有り

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年

DOI： 10.1038/s41598-018-28368-z 　

eISSN：2045-2322
Genome-wide meta-analysis in Japanese populations identifies novel variants at the TMC6-TMC8 and SIX3-SIX2 loci associated with HbA(1c) 査読有り

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年11月

DOI： 10.1038/s41598-017-16493-0 　

ISSN：2045-2322
Detecting genetic association through shortest paths in a bidirected graph 査読有り

Masao Ueki, Yoshinori Kawasaki, Gen Tamiya

GENETIC EPIDEMIOLOGY　41　(6)　481-497　2017年9月

DOI： 10.1002/gepi.22051 　

ISSN：0741-0395

eISSN：1098-2272
Security controls in an integrated Biobank to protect privacy in data sharing: rationale and study design 査読有り

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年7月

DOI： 10.1186/s12911-017-0494-5 　

ISSN：1472-6947
Whole-exome sequencing confirmation of multiple MC1R variants associated with extensive freckles and red hair: Analysis of a Mongolian family 査読有り

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年11月

DOI： 10.1016/j.jdermsci.2016.08.009 　

ISSN：0923-1811

eISSN：1873-569X
The Tohoku Medical Megabank Project: Design and Mission 査読有り

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年9月

DOI： 10.2188/jea.JE20150268 　

ISSN：0917-5040
Smooth-Threshold Multivariate Genetic Prediction with Unbiased Model Selection 査読有り

Masao Ueki, Gen Tamiya

GENETIC EPIDEMIOLOGY　40　(3)　233-243　2016年4月

DOI： 10.1002/gepi.21958 　

ISSN：0741-0395

eISSN：1098-2272
Analysis of the genes responsible for steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis in Japanese patients by whole-exome sequencing analysis 査読有り

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年2月

DOI： 10.1038/jhg.2015.122 　

ISSN：1434-5161

eISSN：1435-232X
Waardenburg syndrome type IIE in a Japanese patient caused by a novel missense mutation in the SOX10 gene 査読有り

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年12月

DOI： 10.1111/1346-8138.13095 　

ISSN：0385-2407

eISSN：1346-8138
Immunohistopathological analysis of frizzled-4-positive immature melanocytes from hair follicles of patients with Rhododenol-induced leukoderma 査読有り

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年11月

DOI： 10.1016/j.jdermsci.2015.07.015 　

ISSN：0923-1811

eISSN：1873-569X
Positive selection with diversity in oculocutaneous albinisms type 2 gene (OCA2) among Japanese 査読有り

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

PIGMENT CELL & MELANOMA RESEARCH　28　(2)　233-235　2015年3月

DOI： 10.1111/pcmr.12337 　

ISSN：1755-1471

eISSN：1755-148X
Whole-exome sequencing confirmation of a novel heterozygous mutation in RUNX1 in a pregnant woman with platelet disorder 査読有り

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

PLATELETS　26　(4)　364-369　2015年

DOI： 10.3109/09537104.2014.912750 　

ISSN：0953-7104

eISSN：1369-1635
Association of neonatal hyperbilirubinemia in breast-fed infants with UGT1A1 or SLCOs polymorphisms 査読有り

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年1月

DOI： 10.1038/jhg.2014.98 　

ISSN：1434-5161

eISSN：1435-232X
Likelihood ratio-based integrated personal risk assessment of type 2 diabetes 査読有り

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年10月

DOI： 10.1507/endocrj.EJ14-0271 　

ISSN：0918-8959

eISSN：1348-4540
A Mutation of COX6A1 Causes a Recessive Axonal or Mixed Form of Charcot-Marie-Tooth Disease 査読有り

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年9月

DOI： 10.1016/j.ajhg.2014.07.013 　

ISSN：0002-9297

eISSN：1537-6605
Variants in melanogenesis-related genes associate with skin cancer risk among Japanese populations 査読有り

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年4月

DOI： 10.1111/1346-8138.12432 　

ISSN：0385-2407

eISSN：1346-8138
Pleiotropic Effect of Common Variants at ABO Glycosyltranferase Locus in 9q32 on Plasma Levels of Pancreatic Lipase and Angiotensin Converting Enzyme 査読有り

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年2月

DOI： 10.1371/journal.pone.0055903 　

ISSN：1932-6203
A Pollen Coat-Inducible Autoinhibited Ca2+-ATPase Expressed in Stigmatic Papilla Cells Is Required for Compatible Pollination in the Brassicaceae 査読有り

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年2月

DOI： 10.1105/tpc.113.121350 　

ISSN：1040-4651

eISSN：1532-298X
Gamete Attachment Requires GEX2 for Successful Fertilization in Arabidopsis 査読有り

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

CURRENT BIOLOGY　24　(2)　170-175　2014年1月

DOI： 10.1016/j.cub.2013.11.030 　

ISSN：0960-9822

eISSN：1879-0445
Divergence of East Asians and Europeans Estimated Using Male- and Female-Specific Genetic Markers 査読有り

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年

DOI： 10.1093/gbe/evu027 　

ISSN：1759-6653
Case of a Mongolian child with extensive Mongolian spots in mucopolysaccharidosis type VI: Identification of a novel mutation in the arylsulfatase B gene 査読有り

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

JOURNAL OF DERMATOLOGY　40　(9)　758-+　2013年9月

DOI： 10.1111/1346-8138.12237 　

ISSN：0385-2407

eISSN：1346-8138
Comparison of caregiver strain in Parkinson's disease between Yamagata, Japan, and Maryland, The United States 査読有り

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年6月

DOI： 10.1016/j.parkreldis.2013.02.014 　

ISSN：1353-8020

eISSN：1873-5126
A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy 査読有り

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年5月

DOI： 10.1038/jhg.2013.8 　

ISSN：1434-5161 1435-232X
Association of melanogenesis genes with skin color variation among Japanese females 査読有り

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

Journal of Dermatological Science　69　(2)　167-172　2013年2月

DOI： 10.1016/j.jdermsci.2012.10.016 　

ISSN：0923-1811 1873-569X
Constructing a contemporary gene-environmental cohort : Study design of the Yamagata Molecular Epidemiological Cohort Study. 査読有り

Yamagata University, Genomic Cohort Consortium

J Hum Genet　58　(1)　54-6　2013年

DOI： 10.1038/jhg.2012.128 　
Association of breast-fed neonatal hyperbilirubinemia with UGT1A1 polymorphisms: 211G > A (G71R) mutation becomes a risk factor under inadequate feeding 査読有り

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年1月

DOI： 10.1038/jhg.2012.116 　

ISSN：1434-5161
Generation of a Monoclonal Antibody Specifically Reacting with Neuron-specific TATA-Box Binding Protein-Associated Factor 1 (N-TAF1). 査読有り

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

Antibodies　2　(1)　1-8　2013年
出版者・発行元：
DOI： 10.3390/antib2010001 　

eISSN：2073-4468
The confounding effect of cryptic relatedness for environmental risks of systolic blood pressure on cohort studies. 査読有り

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

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

DOI： 10.1002/mgg3.4 　
HLA-A*0206 with TLR3 Polymorphisms Exerts More than Additive Effects in Stevens-Johnson Syndrome with Severe Ocular Surface Complications 査読有り

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

PLOS ONE　7　(8)　e43650　2012年8月

DOI： 10.1371/journal.pone.0043650 　

ISSN：1932-6203
Sustained expression of a neuron-specific isoform of the Taf1 gene in development stages and aging in mice 査読有り

Jamiyansuren Jambaldorj, Satoshi Makino, Batmunkh Munkhbat, Gen Tamiya

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　425　(2)　273-277　2012年8月

DOI： 10.1016/j.bbrc.2012.07.081 　

ISSN：0006-291X
Epistatic interaction between Toll-like receptor 3 (TLR3) and prostaglandin E receptor 3 (PTGER3) genes 査読有り

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年5月

DOI： 10.1016/j.jaci.2012.01.069 　

ISSN：0091-6749
Ultrahigh-dimensional variable selection method for whole-genome gene-gene interaction analysis 査読有り

Masao Ueki, Gen Tamiya

BMC BIOINFORMATICS　13　(1)　72　2012年5月

DOI： 10.1186/1471-2105-13-72 　

ISSN：1471-2105
UBR5 Gene Mutation Is Associated with Familial Adult Myoclonic Epilepsy in a Japanese Family. 査読有り

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

ISRN Neurol　2012　508308-4　2012年
出版者・発行元：
DOI： 10.5402/2012/508308 　

eISSN：2090-5513
Polymorphism of proinflammatory cytokine genes and albuminuria in the Japanese general population: the Takahata study 査読有り

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年12月

DOI： 10.1093/ndt/gfr105 　

ISSN：0931-0509
Impaired Glucose Metabolism Slows Executive Function Independent of Cerebral Ischemic Lesions in Japanese Elderly: The Takahata Study 査読有り

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年

DOI： 10.2169/internalmedicine.50.4871 　

ISSN：0918-2918
Identification of MICA as a Susceptibility Gene for Pulmonary Mycobacterium avium Complex Infection 査読有り

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年6月

DOI： 10.1086/598982 　

ISSN：0022-1899
Transcriptional dysregulation: a cause of dystonia? 査読有り

Gen Tamiya

LANCET NEUROLOGY　8　(5)　416-418　2009年5月

DOI： 10.1016/S1474-4422(09)70087-0 　

ISSN：1474-4422
Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice 査読有り

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年8月

DOI： 10.1002/hep.22365 　

ISSN：0270-9139
Genetic analysis of craniofacial traits in the medaka 査読有り

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

GENETICS　177　(4)　2379-2388　2007年12月

DOI： 10.1534/genetics.106.068460 　

ISSN：0016-6731
Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity 査読有り

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年11月

DOI： 10.1007/s10038-007-0193-7 　

ISSN：1434-5161
Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism 査読有り

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年3月

DOI： 10.1086/512129 　

ISSN：0002-9297
Synergistic association of mitochondrial uncoupling protein (UCP) genes with schizophrenia 査読有り

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年3月

DOI： 10.1002/ajmg.b.30443 　

ISSN：1552-4841
TAF1 as the most plausible disease gene for XDP/DYT3 [4] 査読有り

Gen Tamiya, Satoshi Makino, Ryuji Kaji

American Journal of Human Genetics　81　(2)　417-418　2007年
出版者・発行元： University of Chicago Press
DOI： 10.1086/519531 　

ISSN：0002-9297
Genomewide association analysis of human narcolepsy and a new resistance gene 査読有り

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年8月

DOI： 10.1086/505539 　

ISSN：0002-9297
Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice 査読有り

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年3月

DOI： 10.1136/gut.2005.071118 　

ISSN：0017-5749
Genetic linkage map of medaka with polymerase chain reaction length polymorphisms 査読有り

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年12月

DOI： 10.1016/j.gene.2005.07.043 　

ISSN：0378-1119
Gene expression profiling of Japanese psoriatic skin reveals an increased activity in molecular stress and immune response signals 査読有り

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年12月

DOI： 10.1007/s00109-005-0721-x 　

ISSN：0946-2716
AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats 査読有り

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年12月

DOI： 10.1097/01.alc.0000191126.11479.69 　

ISSN：0145-6008
Molecular dissection and anatomical basis of dystonia: X-linked recessive dystonia-parkinsonism (DYT3) 査読有り

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

Journal of Medical Investigation　52　280-283　2005年11月

DOI： 10.2152/jmi.52.280 　

ISSN：1343-1420
Immunohistochemical study TAFII250 in the rat laryngeal of nervous system 査読有り

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年10月

DOI： 10.14670/HH-20.1029 　

ISSN：0213-3911
Genetic features of Khoton Mongolians revealed by SNP analysis of the X chromosome 査読有り

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年9月

DOI： 10.1016/j.gene.2005.06.029 　

ISSN：0378-1119
Whole genome association study of rheumatoid arthritis using 27 039 microsatellites 査読有り

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年8月

DOI： 10.1093/hmg/ddi234 　

ISSN：0964-6906
Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism 査読有り

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年7月

DOI： 10.1002/ana.20513 　

ISSN：0364-5134
Genetic features of Mongolian ethnic groups revealed by Y-chromosomal analysis 査読有り

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年2月

DOI： 10.1016/j.gene.2004.10.023 　

ISSN：0378-1119
Identification and characterization of novel variants of the thioredoxin reductase 3 new transcript 1 TXNRD3NT1 査読有り

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年1月

DOI： 10.1007/s00335-004-2416-y 　

ISSN：0938-8990
Identification, expression analysis and polymorphism of a novel RLTPR gene encoding a RGD motif, tropomodulin domain and proline/leucine-rich regions 査読有り

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

GENE　343　(2)　291-304　2004年12月

DOI： 10.1016/j.gene.2004.09.004 　

ISSN：0378-1119
Leptin deficiency enhances sensitivity of rats to alcoholic steatohepatitis through suppression of metallothionein 査読有り

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年11月

DOI： 10.1152/ajpgi.00107.2004 　

ISSN：0193-1857
hRDH-E2 gene polymorphisms, variable transcriptional start sites, and psoriasis 査読有り

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年8月

DOI： 10.1007/s00335-004-2349-5 　

ISSN：0938-8990
Integrative annotation of 21,037 human genes validated by full-length cDNA clones 査読有り

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年6月

DOI： 10.1371/journal.pbio.0020162 　

ISSN：1545-7885
Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world 査読有り

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年5月

DOI： 10.1086/420793 　

ISSN：0002-9297
Notes on the maximum likelihood estimation of haplotype frequencies 査読有り

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年5月

DOI： 10.1046/j.1529-8817.2003.00088.x 　

ISSN：0003-4800
Identification of two new C4 alleles by DNA sequencing and evidence for a historical recombination of serologically defined C4A and C4B alleles 査読有り

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年3月

DOI： 10.1111/j.1399-0039.2004.0175.x 　

ISSN：0001-2815
Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met 査読有り

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年3月

DOI： 10.1053/j.gastro.2003.12.008 　

ISSN：0016-5085
Novel algorithm for automated genotyping of microsatellites 査読有り

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年

DOI： 10.1093/nar/gkh946 　

ISSN：0305-1048
Identification of NAD(+)-dependent isocitrate dehydrogenase 3 gamma-like (IDH3GL) gene and its genetic polymorphisms 査読有り

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

GENE　323　141-148　2003年12月

DOI： 10.1016/j.gene.2003.09.014 　

ISSN：0378-1119
Toward identification of susceptibility genes for sporadic Parkinson's disease 査読有り

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

JOURNAL OF NEUROLOGY　250　40-43　2003年10月

DOI： 10.1007/s00415-003-1307-6 　

ISSN：0340-5354
Corneodesmosin gene: no evidence for PSORS 1 gene in North-eastern Thai psoriasis patients 査読有り

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年9月

DOI： 10.1034/j.1399-0039.2003.00056.x 　

ISSN：0001-2815
Localization of a non-melanoma skin cancer susceptibility region within the major histocompatibility complex by association analysis using microsatellite markers 査読有り

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年3月

DOI： 10.1034/j.1399-0039.2003.00007.x 　

ISSN：0001-2815
Identification of I kappa BL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis 査読有り

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年2月

DOI： 10.1086/346067 　

ISSN：0002-9297
SLURP-2, a novel member of the human Ly-6 superfamily that is up-regulated in psoriasis vulgaris 査読有り

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

GENOMICS　81　(1)　26-33　2003年1月

DOI： 10.1016/S0888-7543(02)00025-3 　

ISSN：0888-7543
Identification of the hRDH-E2 gene, a novel member of the SDR family, and its increased expression in psoriatic lesion 査読有り

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

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

DOI： 10.1016/S0006-291X(02)02344-6 　

ISSN：0006-291X
Genetic isolates in East Asia: A study of linkage disequilibrium in the X chromosome 査読有り

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年8月

DOI： 10.1086/341608 　

ISSN：0002-9297
Identification of novel candidate genes in the diffuse panbronchiolitis critical region of the class I human MHC 査読有り

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年8月

DOI： 10.1007/s00251-002-0470-8 　

ISSN：0093-7711
Susceptibility locus for non-obstructive azoospermia is localized within the HLA-DR/DQ subregion: Primary role of DQB1*0604 査読有り

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年7月

DOI： 10.1034/j.1399-0039.2002.600107.x 　

ISSN：0001-2815
Corneodesmosin DNA polymorphisms in MHC haplotypes and Japanese patients with psoriasis 査読有り

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年7月

DOI： 10.1034/j.1399-0039.2002.600110.x 　

ISSN：0001-2815
Association of a determinant on mouse chromosome 18 with experimental severe Plasmodium berghei malaria 査読有り

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

INFECTION AND IMMUNITY　70　(2)　512-516　2002年2月

DOI： 10.1128/IAI.70.2.512-516.2002 　

ISSN：0019-9567
Genomic anatomy of a premier major histocompatibility complex paralogous region on chromosome 1q21-q22 査読有り

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年5月

DOI： 10.1101/gr.175801 　

ISSN：1088-9051
New polymorphic microsatellite markers in the human MHC class III region 査読有り

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年5月

DOI： 10.1034/j.1399-0039.2001.057005397.x 　

ISSN：0001-2815
Bioinformatics issues for automating the annotation of genomic sequences. 査読有り

Carter K, Oka A, Tamiya G, Bellgard MI

Genome Inform Ser　12　204-11　2001年

DOI： 10.11234/gi1990.12.204 　
New polymorphic microsatellite markers in the human MHC class II region 査読有り

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

TISSUE ANTIGENS　56　(6)　492-500　2000年12月

DOI： 10.1034/j.1399-0039.2000.560602.x 　

ISSN：0001-2815
Genomic organization, chromosomal localization, and the complete 22 kb DNA sequence of the human GCMa/GCM1, a placenta-specific transcription factor gene 査読有り

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年11月

DOI： 10.1006/bbrc.2000.3775 　

ISSN：0006-291X
Gene structure and promoter for Crad2 encoding mouse cis-retinol/3 alpha-hydroxysterol short-chain dehydrogenase isozyme 査読有り

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年6月

DOI： 10.1016/S0378-1119(00)00194-3 　

ISSN：0378-1119
Fine localization of a major disease-susceptibility locus for diffuse panbronchiolitis 査読有り

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年2月

DOI： 10.1086/302786 　

ISSN：0002-9297
Molecular dynamics of MHC genesis unraveled by sequence analysis of the 1,796,938-bp HLA class I region 査読有り

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年11月

DOI： 10.1073/pnas.96.23.13282 　

ISSN：0027-8424
Association analysis using refined microsatellite markers localizes a susceptibility locus for psoriasis vulgaris within a 111 kb segment telomeric to the HLA-C gene 査読有り

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年11月

DOI： 10.1093/hmg/8.12.2165 　

ISSN：0964-6906
Complete sequence and gene map of a human major histocompatibility complex 査読有り

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年10月

DOI： 10.1038/44853 　

ISSN：0028-0836
New polymorphic microsatellite markers in the human MHC class I region 査読有り

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年9月

DOI： 10.1034/j.1399-0039.1999.540302.x 　

ISSN：0001-2815
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 査読有り

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年5月

DOI： 10.1086/302364 　

ISSN：0002-9297
Genome sequencing analysis of the 1.8 Mb entire human MHC class I region 査読有り

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

IMMUNOLOGICAL REVIEWS　167　193-199　1999年2月

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

ISSN：0105-2896
Physical mapping between the S and HLA-E genes in the human MHC class I region: construction of a BAC, PAC, and cosmid contig 査読有り

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年11月

DOI： 10.1007/s002510050451 　

ISSN：0093-7711
Microsatellite polymorphism within the MICB gene among Japanese patients with Behcet's disease 査読有り

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年8月

DOI： 10.1016/S0198-8859(98)00047-0 　

ISSN：0198-8859
Twenty-six new polymorphic microsatellite markers around the HLA-B, -C and -E loci in the human MHC class I region 査読有り

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

TISSUE ANTIGENS　51　(4)　337-346　1998年4月

ISSN：0001-2815
Nucleotide sequencing analysis of the 146-kilobase segment around the IkBL and MICA genes at the centromeric end of the HLA class I region 査読有り

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年2月

DOI： 10.1006/geno.1997.5114 　

ISSN：0888-7543
An embryological study of ventralization of dorsal structures in the tail of medaka (Oryzias latipes) Da mutants 査読有り

G Tamiya, Y Wakamatsu, K Ozato

DEVELOPMENT GROWTH & DIFFERENTIATION　39　(4)　531-538　1997年8月

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

ISSN：0012-1592
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 査読有り

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

GENOMICS　42　(3)　422-435　1997年6月

DOI： 10.1006/geno.1997.4745 　

ISSN：0888-7543
Genomic structure of the human MHC class I MICB gene 査読有り

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

IMMUNOGENETICS　45　(2)　161-162　1996年

DOI： 10.1007/s002510050184 　

ISSN：0093-7711
An efficient expression vector for transgenic medaka construction. 査読有り

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年

︎全件表示 ︎最初の5件までを表示

MISC 6

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年4月
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年2月
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年1月
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年7月
統計的機械学習によるゲノムリスク予測

田宮元, 植木優夫

Precision Medicine　2　(12)　23-26　2019年11月
バイオバンク・ゲノムコホートデータの人工知能解析

田宮元

実験医学　37　(16)　2712-2713　2019年10月

︎全件表示 ︎最初の5件までを表示

書籍等出版物 5

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年9月

ISBN: 9784758122665
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年7月

ISBN: 4254122292
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年4月

ISBN: 4944157630
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年3月

ISBN: 9784320111172
予防医学辞典

田宮元

朝倉書店　2005年5月

ISBN: 4254300816

共同研究・競争的資金等の研究課題 5

マルチスケール精神病データの疎性モデリング解析競争的資金

田宮元

提供機関：文部科学省

制度名：科学研究費補助金新学術領域研究(研究領域提案型)

2019年4月～ 2021年3月
深層学習による大規模ゲノムコホート解析競争的資金

田宮元

提供機関：日本学術振興会

制度名：科学研究費補助金基盤研究(C)

2016年4月～ 2019年3月
スパースモデリングによる大規模ゲノムコホート解析競争的資金

田宮元

提供機関：文部科学省

制度名：科学研究費補助金新学術領域研究(研究領域提案型)

2016年4月～ 2018年3月
ゲノムコホート研究のための遺伝統計学競争的資金

田宮元

提供機関：日本学術振興会

制度名：科学研究費補助金基盤研究(C)

2013年4月～ 2016年3月
パーソナルゲノム情報のための遺伝統計手法の開発競争的資金

田宮元

提供機関：文部科学省

制度名：科学研究費補助金新学術領域研究(研究領域提案型)

2013年4月～ 2015年3月