多祖先全基因组关联分析确定类风湿关节炎的新遗传机制

　　美国里格姆妇女医院Soumya Raychaudhuri和日本大阪大学医学院Yukinori Okada共同合作近期取得重要工作进展，他们通过多祖先全基因组关联分析确定了类风湿关节炎的新遗传机制。相关论文2022年11月4日在线发表于《自然—遗传学》杂志上。

　　研究人员提出了一项大规模的RA全基因组关联研究（GWAS），其中包括来自五个祖先群体的276020个样本。通过多祖先荟萃分析，他们确定了124个位点（P<5×10−8） ，其中34个是新发现的。新基因座上的候选基因表明，免疫系统（如TNIP2和TNFRSF11A）和关节组织（如WISP1）在RA病因学中起着重要作用。多祖先精细映射确定了假定因果变异（如LEF1）。

　　此外，基于多血统GWAS的PRS优于基于单血统GWAS的PRS，并且在欧洲和东亚血统人群之间具有可比性。他们的研究为RA的病因提供了一些见解，并提高了RA的遗传可预测性。

　　据介绍，类风湿性关节炎（RA）是一种病因不明的高度遗传性复杂疾病。RA的多祖先遗传研究有望提高检测遗传信号的能力、精细定位分辨率和多基因风险评分（PRS）的性能。

　　附：英文原文

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

　　Author: Ishigaki, Kazuyoshi, Sakaue, Saori, Terao, Chikashi, Luo, Yang, Sonehara, Kyuto, Yamaguchi, Kensuke, Amariuta, Tiffany, Too, Chun Lai, Laufer, Vincent A., Scott, Ian C., Viatte, Sebastien, Takahashi, Meiko, Ohmura, Koichiro, Murasawa, Akira, Hashimoto, Motomu, Ito, Hiromu, Hammoudeh, Mohammed, Emadi, Samar Al, 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., 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 I., Keystone, Edward, Wolbink, Gertjan, van der Horst-Bruinsma, Irene, Cui, Jing, Liao, Katherine P., Carroll, Robert J., Lee, Hye-Soon, Bang, So-Young, Siminovitch, Katherine A., de Vries, Niek

　　Issue&Volume: 2022-11-04

　　Abstract: 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<5×108), 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.

　　DOI: 10.1038/s41588-022-01213-w

　　Source: https://www.nature.com/articles/s41588-022-01213-w