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

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. © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Kazuyoshi Ishigaki, Saori Sakaue, Chikashi Terao, Yang Luo, Kyuto Sonehara, Kensuke Yamaguchi, Tiffany Amariuta, Chun Lai Too, Vincent A Laufer, Ian C Scott, Sebastien Viatte, Meiko Takahashi, Koichiro Ohmura, Akira Murasawa, Motomu Hashimoto, Hiromu Ito, Mohammed Hammoudeh, Samar Al Emadi, Basel K Masri, Hussein Halabi, Humeira Badsha, Imad W Uthman, Xin Wu, Li Lin, Ting Li, Darren Plant, Anne Barton, Gisela Orozco, Suzanne M M Verstappen, John Bowes, Alexander J MacGregor, Suguru Honda, Masaru Koido, Kohei Tomizuka, Yoichiro Kamatani, Hiroaki Tanaka, Eiichi Tanaka, Akari Suzuki, Yuichi Maeda, Kenichi Yamamoto, Satoru Miyawaki, Gang Xie, Jinyi Zhang, Christopher I Amos, Edward Keystone, Gertjan Wolbink, Irene van der Horst-Bruinsma, Jing Cui, Katherine P Liao, Robert J Carroll, Hye-Soon Lee, So-Young Bang, Katherine A Siminovitch, Niek de Vries, Lars Alfredsson, Solbritt Rantapää-Dahlqvist, Elizabeth W Karlson, Sang-Cheol Bae, Robert P Kimberly, Jeffrey C Edberg, Xavier Mariette, Tom Huizinga, Philippe Dieudé, Matthias Schneider, Martin Kerick, Joshua C Denny, BioBank Japan Project, Koichi Matsuda, Keitaro Matsuo, Tsuneyo Mimori, Fumihiko Matsuda, Keishi Fujio, Yoshiya Tanaka, Atsushi Kumanogoh, Matthew Traylor, Cathryn M Lewis, Stephen Eyre, Huji Xu, Richa Saxena, Thurayya Arayssi, Yuta Kochi, Katsunori Ikari, Masayoshi Harigai, Peter K Gregersen, Kazuhiko Yamamoto, S Louis Bridges, Leonid Padyukov, Javier Martin, Lars Klareskog, Yukinori Okada, Soumya Raychaudhuri. Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis. Nature genetics. 2022 Nov;54(11):1640-1651

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PMID: 36333501

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