Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.,Nature Genetics

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Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.
Nature Genetics ( IF 31.7 ) Pub Date : 2020-06-08 , DOI: 10.1038/s41588-020-0640-3
Kazuyoshi Ishigaki _{1,

2,

3,

4} , Masato Akiyama _{1,

5} , Masahiro Kanai _{1,

4,

6} , Atsushi Takahashi _{1,

7} , Eiryo Kawakami _{8,

9,

10} , Hiroki Sugishita ₉ , Saori Sakaue _{1,

11,

12} , Nana Matoba _{1,

13} , Siew-Kee Low _{1,

14} , Yukinori Okada _{1,

11,

15,

16} , Chikashi Terao ₁₇ , Tiffany Amariuta _{2,

3,

4,

6,

18} , Steven Gazal _{4,

19} , Yuta Kochi _{20,

21} , Momoko Horikoshi ₂₂ , Ken Suzuki _{1,

11,

22,

23} , Kaoru Ito ₂₄ , Satoshi Koyama ₂₄ , Kouichi Ozaki ₂₅ , Shumpei Niida ₂₅ , Yasushi Sakata ₂₆ , Yasuhiko Sakata ₂₇ , Takashi Kohno ₂₈ , Kouya Shiraishi ₂₈ , Yukihide Momozawa ₂₉ , Makoto Hirata ₃₀ , Koichi Matsuda ₃₁ , Masashi Ikeda ₃₂ , Nakao Iwata ₃₂ , Shiro Ikegawa ₃₃ , Ikuyo Kou ₃₃ , Toshihiro Tanaka _{34,

35} , Hidewaki Nakagawa ₃₆ , Akari Suzuki ₂₀ , Tomomitsu Hirota ₃₇ , Mayumi Tamari ₃₇ , Kazuaki Chayama ₃₈ , Daiki Miki ₃₈ , Masaki Mori ₃₉ , Satoshi Nagayama ₄₀ , Yataro Daigo _{41,

42} , Yoshio Miki ₄₃ , Toyomasa Katagiri ₄₄ , Osamu Ogawa ₄₅ , Wataru Obara ₄₆ , Hidemi Ito _{47,

48} , Teruhiko Yoshida ₄₉ , Issei Imoto _{50,

51,

52} , Takashi Takahashi ₅₃ , Chizu Tanikawa ₅₄ , Takao Suzuki ₅₅ , Nobuaki Sinozaki ₅₅ , Shiro Minami ₅₆ , Hiroki Yamaguchi ₅₇ , Satoshi Asai _{58,

59} , Yasuo Takahashi ₅₉ , Ken Yamaji ₆₀ , Kazuhisa Takahashi ₆₁ , Tomoaki Fujioka ₄₆ , Ryo Takata ₄₆ , Hideki Yanai ₆₂ , Akihide Masumoto ₆₃ , Yukihiro Koretsune ₆₄ , Hiromu Kutsumi ₆₅ , Masahiko Higashiyama ₆₆ , Shigeo Murayama ₆₇ , Naoko Minegishi ₆₈ , Kichiya Suzuki ₆₈ , Kozo Tanno ₆₉ , Atsushi Shimizu ₆₉ , Taiki Yamaji ₇₀ , Motoki Iwasaki ₇₀ , Norie Sawada ₇₀ , Hirokazu Uemura _{71,

72} , Keitaro Tanaka ₇₃ , Mariko Naito _{74,

75} , Makoto Sasaki ₆₉ , Kenji Wakai ₇₄ , Shoichiro Tsugane ₇₆ , Masayuki Yamamoto ₆₈ , Kazuhiko Yamamoto ₂₀ , Yoshinori Murakami ₇₇ , Yusuke Nakamura ₇₈ , Soumya Raychaudhuri _{2,

3,

4,

6,

79} , Johji Inazawa _{80,

81} , Toshimasa Yamauchi ₂₃ , Takashi Kadowaki ₂₃ , Michiaki Kubo ₈₂ , Yoichiro Kamatani _{1,

83}

Affiliation

Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Center for Data Sciences, Harvard Medical School, Boston, MA, USA.
Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
Medical Sciences Innovation Hub Program (MIH), RIKEN, Yokohama, Japan.
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Genetics and UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
Laboratory of Statistical Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Graduate School of Arts and Sciences, Harvard University, Cambridge, MA, USA.
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Laboratory for Genomics of Diabetes and Metabolism, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Medical Genome Center, National Center for Geriatrics and Gerontology, Obu, Japan.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Tohoku, Japan.
Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan.
Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
Laboratory for Respiratory and Allergic Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of Surgery and Sciences, Graduate School of Medicine, Kyushu University, Fukuoka, Japan.
Department of Gastroenterological Surgery, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
Department of Medical Oncology and Cancer Center, and Center for Advanced Medicine against Cancer, Shiga University of Medical Science, Shiga, Japan.
Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Department of Genetic Diagnosis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan.
Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Urology, Iwate Medical University School of Medicine, Iwate, Japan.
Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, Japan.
Division of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
Division of Molecular Genetics, Aichi Cancer Center Research Institute, Nagoya, Japan.
Risk Assessment Center, Aichi Caner Center Hospital, Nagoya, Japan.
Division of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Aichi Cancer Center, Nagoya, Japan.
Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Tokushukai Group, Tokyo, Japan.
Department of Bioregulation, Nippon Medical School, Kawasaki, Japan.
Department of Hematology, Nippon Medical School, Tokyo, Japan.
Division of Pharmacology, Department of Biomedical Science, Nihon University School of Medicine, Tokyo, Japan.
Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Tokyo, Japan.
Department of Internal Medicine and Rheumatology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.
Aso Iizuka Hospital, Fukuoka, Japan.
National Hospital Organization Osaka National Hospital, Osaka, Japan.
Center for Clinical Research and Advanced Medicine, Shiga University of Medical Science, Shiga, Japan.
Department of General Thoracic Surgery, Osaka International Cancer Institute, Osaka, Japan.
Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.
Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.
Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
Department of Preventive Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
College of Nursing Art and Science, University of Hyogo, Akashi, Japan.
Department of Preventive Medicine, Saga University Faculty of Medicine, Saga, Japan.
Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Oral Epidemiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10⁻⁹). East Asian–specific missense variants were identified as candidate causal variants for three novel loci, and we successfully replicated two of them by analyzing independent Japanese cohorts; p.R220W of ATG16L2 (associated with coronary artery disease) and p.V326A of POT1 (associated with lung cancer). We further investigated enrichment of heritability within 2,868 annotations of genome-wide transcription factor occupancy, and identified 378 significant enrichments across nine diseases (false discovery rate < 0.05) (for example, NKX3-1 for prostate cancer). This large-scale GWAS in a Japanese population provides insights into the etiology of complex diseases and highlights the importance of performing GWAS in non-European populations.

中文翻译：

在日本人群中进行的大规模全基因组关联研究确定了跨不同疾病的新型易感基因座。

当前遗传学研究的绝大多数参与者都来自欧洲。为了阐明东亚人群的疾病生物学，我们对212,453名日本人进行了42种疾病的全基因组关联研究（GWAS）。我们在276个基因座中检测到320个独立信号，涉及27种疾病，其中25个是新的基因座（P <9.58×10 ^-9）。东亚特定的错义变体被确定为三个新基因座的候选因果变体，我们通过分析独立的日本队列成功地复制了其中两个。ATG16L2的p.R220W（与冠状动脉疾病相关）和POT1的p.V326A（与肺癌有关）。我们进一步调查了全基因组转录因子占用的2868个注释中的遗传力富集，并确定了九种疾病的378个显着富集（错误发现率<0.05）（例如，前列腺癌的NKX3-1）。日本人群中的这种大型GWAS提供了对复杂疾病的病因学的见识，并强调了在非欧洲人群中进行GWAS的重要性。

更新日期：2020-06-08

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