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Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis

By 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, Hussien Halabi, Humeria Badsha, Imad W Uthman, Xin Wu, Li Lin, Ting Lin, Darren Plant, Anne Barton, Gisela Orozco, Suzanne MM 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, Ed 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 Dieude, Matthias Schneider, Martin Kerick, Joshua C Denny, The Biobank Japan Project, Koichi Matsuda, Keitaro Matsuo, Tsuneyo Mimori, Fumihiko Matsuda, Keishi Fujio, Yoshiya Tanaka, Atsushi Kumanogoh, Matthew Traylor, Cathryn 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

Posted 05 Dec 2021
medRxiv DOI: 10.1101/2021.12.01.21267132

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 x 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.

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