Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis

Ishigaki, Kazuyoshi, Sakaue, Saori, Terao, Chikashi, Luo, Yang, Sonehara, Kyuto, Yamaguchi, Kensuke, Amariuta, Tiffany, Too, Chun Lai, Laufer, Vincent A., Scott, Ian, Viatte, Sebastien, Takahashi, Meiko, Ohmura, Koichiro, Murasawa, Akira, Hashimoto, Motomu, Ito, Hiromu, Hammoudeh, Mohammed, Al Emadi, Samar, Masri, Basel K., Halabi, Hussein, Badsha, Humeira, Uthman, Imad W., Wu, Xin, Lin, Li, Li, Ting, Plant, Darren, Barton, Anne, Orozco, Gisela, Verstappen, Suzanne M. M., Bowes, John, MacGregor, Alexander J. ORCID:, Honda, Suguru, Koido, Masaru, Tomizuka, Kohei, Kamatani, Yoichiro, Tanaka, Hiroaki, Tanaka, Eiichi, Suzuki, Akari, Maeda, Yuichi, Yamamoto, Kenichi, Miyawaki, Satoru, Xie, Gang, Zhang, Jinyi, Amos, Christopher, Keystone, Edward, Wolbink, Gertjan, Horst-Bruinsma, Irene van der, Cui, Jing, Liao, Katherine, Carroll, Robert J. and Lee, Hye-Soon (2022) Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis. Nature Genetics, 54 (11). pp. 1640-1651. ISSN 1061-4036

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Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P < 5 × 10 −8), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.

Item Type: Article
Additional Information: Funding Information: The authors thank the Director of Health Malaysia for supporting the work described in the South Asian (SAS) population: the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) study. The MyEIRA study was funded by grants from Ministry of Health Malaysia (NMRR-08-820-1975) and the Swedish National Research Council (DNR-348-2009-6468). The GENRA study and the CARDERA genetics cohort genotyping were funded by Versus Arthritis (grant reference 19739 to I.C.S.). The Nurses’ Health Study (NHS cohort) is funded by the National Institutes of Health (NIH) (R01 AR049880, UM1 CA186107, R01 CA49449, U01 CA176726 and R01 CA67262). The Swedish EIRA study was supported by the Swedish Research Council (to L.K., L.P. and L.A.). S.S. was in part supported by the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Kanae Foundation for the Promotion of Medical Science, Astellas Foundation for Research on Metabolic Disorders, JCR Grant for Promoting Basic Rheumatology, and Manabe Scholarship Grant for Allergic and Rheumatic Diseases. I.C.S. is funded by the National Institute for Health and Care Research (NIHR) Advanced Research Fellowship (grant reference NIHR300826). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. K.A.S. is supported by the Sherman Family Chair in Genomic Medicine and by a Canadian Institutes for Health Research Foundation Grant (FDN 148457) and grants from the Ontario Research Fund (RE-09-090) and Canadian Foundation for Innovation (33374). S.-C.B. is supported by the Basic Science Research Program through the NRF funded by the Ministry of Education (NRF-2021R1A6A1A03038899). R.P.K. and J.C.E. are funded by NIH (UL1 TR003096). C.M.L. is partly funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. T. Arayssi was partially supported by the National Priorities Research Program (grant 4-344-3-105 from the Qatar National Research Fund, a member of Qatar Foundation). M. Kerick and J.M. are funded by Rheumatology Cooperative Research Thematic Network program RD16/0012/0013 from the Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation). Y.O. is funded by JSPS KAKENHI (19H01021 and 20K21834), AMED (JP21km0405211, JP21ek0109413, JP21ek0410075, JP21gm4010006 and JP21km0405217), JST Moonshot R&D (JPMJMS2021 and JPMJMS2024), Takeda Science Foundation, and the Bioinformatics Initiative of Osaka University Graduate School of Medicine. Y. Kochi is funded by grants from Nanken-Kyoten, TMDU and Medical Research Center Initiative for High Depth Omics. S.R. is supported by UH2AR067677, U01HG009379, R01AR063759 and U01HG012009.
Uncontrolled Keywords: genetics ,/dk/atira/pure/subjectarea/asjc/1300/1311
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging
Faculty of Science > Research Groups > Norwich Epidemiology Centre
Faculty of Medicine and Health Sciences > Research Groups > Norwich Epidemiology Centre
Faculty of Medicine and Health Sciences > Research Groups > Epidemiology and Public Health
Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine
Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine
Faculty of Medicine and Health Sciences > Research Groups > Public Health and Health Services Research (former - to 2023)
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Depositing User: LivePure Connector
Date Deposited: 17 May 2023 15:30
Last Modified: 17 May 2023 15:30
DOI: 10.1038/s41588-022-01213-w

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