Trans-ancestry genome-wide association study identifies novel genetic mechanisms in rheumatoid arthritis
Ishigaki, K.; Sakaue, S.; Terao, C.; Luo, Y.; Sonehara, K.; Yamaguchi, K.; Amariuta, T.; Too, C. L.; Laufer, V. A.; Scott, I. C.; Viatte, S.; Takahashi, M.; Ohmura, K.; Murasawa, A.; Hashimoto, M.; Ito, H.; Hammoudeh, M.; Al Emadi, S.; Masri, B. K.; Halabi, H.; Badsha, H.; Uthman, I. W.; Wu, X.; Lin, L.; Lin, T.; Plant, D.; Barton, A.; Orozco, G.; Verstappen, S. M.; Bowes, J.; MacGregor, A. J.; Honda, S.; Koido, M.; Tomizuka, K.; Kamatani, Y.; Tanaka, H.; Tanaka, E.; Suzuki, A.; Maeda, Y.; Yamamoto, K.; Miyawaki, S.; Xie, G.; Zhang, J.; Amos, C.; Keystone, E.; Wolbink, G.; van der Horst-Bruins
Show 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 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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