Genome-wide association study in a Korean population identifies six novel susceptibility loci for rheumatoid arthritis

Abstract

ObjectiveGenome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case–control population.MethodsWe newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations.ResultsWe identified six new RA-risk loci (SLAMF6, CXCL13, SWAP70, NFKBIA, ZFP36L1 and LINC00158) with pmeta<5×10−8 and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases.ConclusionThis study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.

Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci

“…Furthermore, chromatin changes on T-cell activation and T reg differentiation were strongly associated with RA variants ( figure 3B ). In addition, this analysis replicated our recent findings on the involvement of two non-immune organs, 8 lung and small intestine, in disease pathogenesis ( figure 3B and online supplemental table S7 ).…”

“…A genome-wide meta-analysis of RA associations in 22 628 patients with RA and 288 664 healthy controls in East Asian (8267 cases and 244 741 controls) and European (14 361 cases and 43 923 controls) populations detected 11 novel loci associated with RA risk at the genome-wide significance level (4.6×10 −8 ≤p meta ≤1.5×10 −10 ), replicating the known RA associations in 71 non-MHC loci 8 36 37 ( figure 1 and online supplemental table S1 ). The meta-analysis association summary statistics in this study are available online ( https://doi.org/10.5061/dryad.ns1rn8pr0 ).…”

“…RA association summary statistics were retrieved from previous GWASs in Korean, Japanese and European populations. 6 8 9 The sample size of each GWAS was considerable (4068 RA cases and 36 487 controls in the Korean population 8 ; 4199 cases and 208 254 controls in the Japanese population 9 ; 14 361 cases and 43 923 controls in the European population 6 ), which brought the final sample size to more than 310 000. The summary statistics from Japanese and European populations were available at the Japanese Encyclopedia of Genetic associations by RIKEN ( http://jenger.riken.jp/en/result ).…”

“…Genotype data of 5288 Korean and 2502 European individuals were used to estimate LD matrices. The Korean genotype/imputation data were previously described in our recent study, 8 and the European genotype data were obtained from European Genome-phenome Archive (EGAD00010000290). 15 We newly imputed untyped variants in the European individuals from quality-controlled variants (with missing rate≤0.05, MAF≥0.5%, and p value in Hardy-Weinberg equilibrium exact test≤1×10 −7 ) in each RA locus using SHAPEIT2 and Minimac3 with the 1KGP imputation reference panel.…”

Altered function and differentiation of age-associated B cells contribute to the female bias in lupus mice

“…The CORO1A-DEF6 blood transcription module correlates with responses to flu vaccination and malaria 25 , 26 . Furthermore, SWAP70 is a susceptibility locus for RA 27 and CVD 28 while DEF6 is a risk factor for human SLE 29 , 30 . Mutations in DEF6 moreover result in early-onset autoimmune manifestations, often associated with viral infections, which include autoantibody production and upregulation of an ISG signature 31 , 32 .…”