Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis
Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis
Abstract Trans-ancestry genetic research promises to improve power to detect genetic signals, fine-mapping resolution, and performances of polygenic risk score (PRS). We here present a large-scale genome-wide association study (GWAS) of rheumatoid arthritis (RA) which includes 276,020 samples of five ancestral groups. We conducted a trans-ancestry meta-analysis and identified 124 loci (P < 5 × 10-8), of which 34 were novel. Candidate genes at the novel loci suggested essential roles of the immune system (e.g., TNIP2 and TNFRSF11A) and joint tissues (e.g., WISP1) in RA etiology. Trans-ancestry fine mapping identified putatively causal variants with biological insights (e.g., LEF1). Moreover, PRS based on trans-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between European and East Asian populations. Our study provides multiple insights into the etiology of RA and improves genetic predictability of RA.
Tanaka Hiroaki、Zhang Jinyi、Orozco Gisela、Tomizuka Kohei、Tanaka Eiichi、de Vries Niek、Padyukov Leonid、Martin Javier、Klareskog Lars、Mariette Xavier、Huizinga Tom、Dieud¨| Philippe、Kerick Martin、The Biobank Japan Project、Matsuda Koichi、Traylor Matthew、Saxena Richa、Xie Gang、van der Horst-Bruinsma Irene、Ito Hiromu、Hammoudeh Mohammed、Masri Basel K、Badsha Humeria、Uthman Imad W、Wu Xin、Lin Li、Cui Jing、Bae Sang-Cheol、Kimberly Robert P、Carroll Robert J、Bang So-Young、Ishigaki Kazuyoshi、Sonehara Kyuto、Yamaguchi Kensuke、Laufer Vincent A、Scott Ian C、Takahashi Meiko、Ohmura Koichiro、Okada Yukinori、Denny Joshua C、Lee Hye-Soon、Matsuo Keitaro、Maeda Yuichi、Arayssi Thurayya、Verstappen Suzanne MM、Rantap??-Dahlqvist Solbritt、Kumanogoh Atsushi、MacGregor Alexander J、Al Emadi Samar、Sakaue Saori、Alfredsson Lars、Kochi Yuta、Matsuda Fumihiko、Liao Katherine P、Luo Yang、Mimori Tsuneyo、Miyawaki Satoru、Ikari Katsunori、Amos Chris、Hashimoto Motomu、Lin Ting、Xu Huji、Yamamoto Kazuhiko、Kamatani Yoichiro、Karlson Elizabeth W、Tanaka Yoshiya、Siminovitch Katherine A、Halabi Hussien、Terao Chikashi、Schneider Matthias、Fujio Keishi、Bowes John、Lewis Cathryn M、Amariuta Tiffany、Barton Anne、Murasawa Akira、Edberg Jeffrey C、Koido Masaru、Honda Suguru、Keystone Ed、Yamamoto Kenichi、Suzuki Akari、Harigai Masayoshi、Plant Darren、Eyre Stephen、Bridges S. Louis Jr、Viatte Sebastien、Wolbink Gertjan、Too Chun Lai、Gregersen Peter K、Raychaudhuri Soumya
The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health JapanLunenfeld-Tanenbaum Research Institute||Department of Medicine, University of TorontoCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre||NIHR Manchester Biomedical Research Centre, Manchester University Foundation TrustLaboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical SciencesInstitute of Rheumatology, Tokyo Women?ˉs Medical University Hospital||Division of Rheumatology, Department of Internal Medicine, Tokyo Women?ˉs Medical University School of MedicineDept Rheumatology, Amsterdam University Medical Centers, AMC & ARCDepartment of Medicine, Division of Rheumatology, Karolinska Institutet and Karolinska University HospitalInstitute of Parasitology and Biomedicine Lopez-Neyra, CSICDepartment of Medicine, Division of Rheumatology, Karolinska Institutet and Karolinska University HospitalDepartment of Rheumatology, Universit¨| Paris-Saclay, Assistance Pubique - H?pitaux de Paris, H?pital Bic¨otre, INSERM UMR1184, Le Kremlin Bic¨otreLeiden University Medical CenterUniversity of Paris||Department of Rheumatology, INSERM U1152, H?pital Bichat-Claude Bernard, APHPInstitute of Parasitology and Biomedicine Lopez-Neyra, CSICInstitute of Medical Science, The University of TokyoLaboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo||Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of TokyoDepartment of Medical & Molecular Genetics, King?ˉs College LondonProgram in Medical and Population Genetics, Broad Institute of Harvard and MITLunenfeld-Tanenbaum Research InstituteDept Rheumatology, Amsterdam University Medical Centers, AMC & ARCDepartment of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine||Department of Orthopaedic Surgery, Kurashiki Central HospitalDepartment of Internal Medicine, Hamad Medical CorporationDepartment of Internal Medicine, Jordan HospitalDr. Humeira Badsha Medical Center, Emirates HospitalDepartment of Rheumatology, American University of BeirutDepartment of Rhuematology and Immunology, Shanghai Changzeng Hospital, The Second Military Medical UniversityDepartment of Rhuematology and Immunology, Shanghai Changzeng Hospital, The Second Military Medical UniversityDivision of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women?ˉs Hospital and Harvard Medical SchoolDepartment of Rheumatology, Hanyang University Hospital for Rheumatic Diseases||Hanyang University Institute for Rheumatology ResearchCenter for Clinical and Translational Science, Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at BirminghamDepartment of Biomedical Informatics, Vanderbilt University School of MedicineDepartment of Rheumatology, Hanyang University Hospital for Rheumatic Diseases||Hanyang University Institute for Rheumatology ResearchCenter for Data Sciences, Brigham and Women?ˉs Hospital and Harvard Medical School||Division of Genetics, Department of Medicine, Brigham and Women?ˉs Hospital, Harvard Medical School||Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical SciencesDepartment of Statistical Genetics, Osaka University Graduate School of Medicine||Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka UniversityDepartment of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University||Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical SciencesDepartment of Clinical Immunology and Rheumatology, University of Alabama at Birmingham School of Medicine||Michigan Medicine Department of PathologyHaywood Academic Rheumatology Centre, Haywood Hospital, Midlands Partnership NHS Foundation Trust||Primary Care Centre Versus Arthritis, School of Medicine, Keele UniversityCenter for Genomic Medicine, Kyoto University Graduate School of MedicineDepartment of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto UniversityDepartment of Statistical Genetics, Osaka University Graduate School of Medicine||Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University||Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University||Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences||Center for Infectious Disease Education and Research (CiDER), Osaka UniversityDepartment of Biomedical Informatics, Vanderbilt University School of Medicine||All of Us Research Program, Office of the Director, National Institutes of Health||Department of Medicine, Vanderbilt University School of MedicineDepartment of Rheumatology, Hanyang University Hospital for Rheumatic Diseases||Hanyang University Institute for Rheumatology ResearchDivision of Cancer Epidemiology and Prevention, Department of Preventive Medicine, Aichi Cancer Center Research Institute||Department of Cancer Epidemiology, Nagoya University Graduate School of MedicineIntegrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University||Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine||Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka UniversityDepartment of Internal Medicine, Weill Cornell Medicine-Qatar, Education CityNIHR Manchester Biomedical Research Centre, Manchester University Foundation Trust||Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, the University of ManchesterDept of Public Health and Clinical Medicine, Rheumatology, Ume? UniversityIntegrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University||Centre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre||Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine||Department of Immunopathology, Immunology Frontier Research Center (WPI-IFReC), Osaka UniversityNorwich Medical School, University of East AngliaDepartment of Internal Medicine, Hamad Medical CorporationCenter for Data Sciences, Brigham and Women?ˉs Hospital and Harvard Medical School||Division of Genetics, Department of Medicine, Brigham and Women?ˉs Hospital, Harvard Medical School||Department of Statistical Genetics, Osaka University Graduate School of Medicine||Program in Medical and Population Genetics, Broad Institute of Harvard and MITDepartment of Environmental Medicine, Karolinska InstitutetDepartment of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University||Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical SciencesCenter for Genomic Medicine, Kyoto University Graduate School of MedicineDivision of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women?ˉs Hospital and Harvard Medical School||Department of Biomedical Informatics, Harvard Medical School||Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Healthcare SystemCenter for Data Sciences, Brigham and Women?ˉs Hospital and Harvard Medical School||Division of Genetics, Department of Medicine, Brigham and Women?ˉs Hospital, Harvard Medical School||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women?ˉs Hospital and Harvard Medical School||Department of Biomedical Informatics, Harvard Medical SchoolDepartment of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto UniversityDepartment of Neurosurgery, Faculty of Medicine, the University of TokyoInstitute of Rheumatology, Tokyo Women?ˉs Medical University Hospital||Department of Orthopedics, Tokyo Women?ˉs Medical University School of Medicine||Division of Multidisciplinary Management of Rheumatic Diseases, Tokyo Women?ˉs Medical UniversityBaylor College of MedicineDepartment of Advanced Medicine for Rheumatic Diseases, Kyoto University Graduate School of Medicine||Department of Clinical Immunology, Graduate School of Medicine, Osaka City UniversityDepartment of Rhuematology and Immunology, Shanghai Changzeng Hospital, The Second Military Medical UniversityDepartment of Rhuematology and Immunology, Shanghai Changzeng Hospital, The Second Military Medical University||School of Clinical Medicine Tsinghua University||Peking-Tsinghua Center for Life Sciences, Tsinghua UniversityLaboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical SciencesLaboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences||Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of TokyoDivision of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women?ˉs Hospital and Harvard Medical SchoolThe First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health JapanLunenfeld-Tanenbaum Research Institute||Departments of Medicine and Immunology, University of TorontoRheumatology Division, Department of Internal Medicine, King Faisal Specialist Hospital and Research CenterLaboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences||Clinical Research Center, Shizuoka General Hospital||The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of ShizuokaDepartment of Rheumatology & Hiller Research Unit Rheumatology, UKD, Heinrich-Heine UniversityDepartment of Allergy and Rheumatology, Graduate School of Medicine, The University of TokyoCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre||NIHR Manchester Biomedical Research Centre, Manchester University Foundation TrustDepartment of Medical & Molecular Genetics, King?ˉs College London||Social, Genetic and Developmental Psychiatry Centre, King?ˉs College LondonCenter for Data Sciences, Brigham and Women?ˉs Hospital and Harvard Medical School||Division of Genetics, Department of Medicine, Brigham and Women?ˉs Hospital, Harvard Medical School||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women?ˉs Hospital and Harvard Medical School||Department of Biomedical Informatics, Harvard Medical School||Department of Epidemiology, Harvard T.H. Chan School of Public HealthCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre||NIHR Manchester Biomedical Research Centre, Manchester University Foundation TrustDepartment of Rheumatology, Niigata Rheumatic CenterCenter for Clinical and Translational Science, Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at BirminghamLaboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical SciencesInstitute of Rheumatology, Tokyo Women?ˉs Medical University Hospital||Division of Rheumatology, Department of Internal Medicine, Tokyo Women?ˉs Medical University School of MedicineUniversity of TorontoDepartment of Statistical Genetics, Osaka University Graduate School of Medicine||Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University||Department of Pediatrics, Osaka University Graduate School of MedicineLaboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical SciencesInstitute of Rheumatology, Tokyo Women?ˉs Medical University Hospital||Division of Rheumatology, Department of Internal Medicine, Tokyo Women?ˉs Medical University School of MedicineCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science CentreCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre||NIHR Manchester Biomedical Research Centre, Manchester University Foundation TrustDepartment of Medicine, Hospital for Special Surgery||Division of Rheumatology, Weill Cornell MedicineCentre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre||Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, The University of Manchester||NIHR Manchester Biomedical Research Centre, Manchester University Foundation TrustDepartment of Rheumatology, Amsterdam Rheumatology and Immunology Center (ARC)Immunogenetics Unit. Allergy and Immunology Research Center. Institute for Medical Research. National Institutes of Health Complex. Ministry of Health||Department of Medicine, Division of Rheumatology, Karolinska Institutet and Karolinska University HospitalRobert S. Boas Center for Genomics and Human Genetics, Feinstein Institutes for Medical ResearchCenter for Data Sciences, Brigham and Women?ˉs Hospital and Harvard Medical School||Division of Genetics, Department of Medicine, Brigham and Women?ˉs Hospital, Harvard Medical School||Program in Medical and Population Genetics, Broad Institute of Harvard and MIT||Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women?ˉs Hospital and Harvard Medical School||Department of Biomedical Informatics, Harvard Medical School||Centre for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre
医学研究方法基础医学内科学
Tanaka Hiroaki,Zhang Jinyi,Orozco Gisela,Tomizuka Kohei,Tanaka Eiichi,de Vries Niek,Padyukov Leonid,Martin Javier,Klareskog Lars,Mariette Xavier,Huizinga Tom,Dieud¨| Philippe,Kerick Martin,The Biobank Japan Project,Matsuda Koichi,Traylor Matthew,Saxena Richa,Xie Gang,van der Horst-Bruinsma Irene,Ito Hiromu,Hammoudeh Mohammed,Masri Basel K,Badsha Humeria,Uthman Imad W,Wu Xin,Lin Li,Cui Jing,Bae Sang-Cheol,Kimberly Robert P,Carroll Robert J,Bang So-Young,Ishigaki Kazuyoshi,Sonehara Kyuto,Yamaguchi Kensuke,Laufer Vincent A,Scott Ian C,Takahashi Meiko,Ohmura Koichiro,Okada Yukinori,Denny Joshua C,Lee Hye-Soon,Matsuo Keitaro,Maeda Yuichi,Arayssi Thurayya,Verstappen Suzanne MM,Rantap??-Dahlqvist Solbritt,Kumanogoh Atsushi,MacGregor Alexander J,Al Emadi Samar,Sakaue Saori,Alfredsson Lars,Kochi Yuta,Matsuda Fumihiko,Liao Katherine P,Luo Yang,Mimori Tsuneyo,Miyawaki Satoru,Ikari Katsunori,Amos Chris,Hashimoto Motomu,Lin Ting,Xu Huji,Yamamoto Kazuhiko,Kamatani Yoichiro,Karlson Elizabeth W,Tanaka Yoshiya,Siminovitch Katherine A,Halabi Hussien,Terao Chikashi,Schneider Matthias,Fujio Keishi,Bowes John,Lewis Cathryn M,Amariuta Tiffany,Barton Anne,Murasawa Akira,Edberg Jeffrey C,Koido Masaru,Honda Suguru,Keystone Ed,Yamamoto Kenichi,Suzuki Akari,Harigai Masayoshi,Plant Darren,Eyre Stephen,Bridges S. Louis Jr,Viatte Sebastien,Wolbink Gertjan,Too Chun Lai,Gregersen Peter K,Raychaudhuri Soumya.Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis[EB/OL].(2025-03-28)[2025-06-13].https://www.medrxiv.org/content/10.1101/2021.12.01.21267132.点此复制
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