Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis
Author:
Ishigaki KazuyoshiORCID, Sakaue SaoriORCID, Terao ChikashiORCID, Luo YangORCID, Sonehara Kyuto, Yamaguchi Kensuke, Amariuta TiffanyORCID, Too Chun LaiORCID, Laufer Vincent A, Scott Ian CORCID, Viatte Sebastien, Takahashi Meiko, Ohmura Koichiro, Murasawa Akira, Hashimoto Motomu, Ito HiromuORCID, Hammoudeh Mohammed, Al Emadi SamarORCID, Masri Basel KORCID, Halabi HussienORCID, Badsha Humeria, Uthman Imad WORCID, Wu Xin, Lin Li, Lin Ting, Plant Darren, Barton Anne, Orozco Gisela, Verstappen Suzanne MM, Bowes JohnORCID, MacGregor Alexander J, 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 ChrisORCID, Keystone Ed, Wolbink Gertjan, van der Horst-Bruinsma IreneORCID, Cui Jing, Liao Katherine PORCID, Carroll Robert J, Lee Hye-Soon, Bang So-Young, Siminovitch Katherine A, de Vries Niek, Alfredsson LarsORCID, Rantapää-Dahlqvist SolbrittORCID, Karlson Elizabeth W, Bae Sang-CheolORCID, Kimberly Robert P, Edberg Jeffrey C, Mariette XavierORCID, Huizinga TomORCID, Dieudé PhilippeORCID, Schneider Matthias, Kerick Martin, Denny Joshua C, Matsuda Koichi, Matsuo KeitaroORCID, Mimori Tsuneyo, Matsuda Fumihiko, Fujio Keishi, Tanaka YoshiyaORCID, Kumanogoh Atsushi, Traylor Matthew, Lewis Cathryn MORCID, Eyre Stephen, Xu Huji, Saxena Richa, Arayssi ThurayyaORCID, Kochi Yuta, Ikari Katsunori, Harigai MasayoshiORCID, Gregersen Peter K, Yamamoto Kazuhiko, Bridges S. LouisORCID, Padyukov LeonidORCID, Martin JavierORCID, Klareskog Lars, Okada YukinoriORCID, Raychaudhuri SoumyaORCID,
Abstract
AbstractTrans-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.
Publisher
Cold Spring Harbor Laboratory
Cited by
14 articles.
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