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

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

Young-Chang Kwon et al. Ann Rheum Dis. 2020 Nov.

Abstract

Objective: Genome-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.

Methods: We 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.

Results: We 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.

Conclusion: This study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.

Keywords: arthritis, rheumatoid; autoimmune diseases; polymorphism, genetic.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1

Genome-wide association analysis results for RA in a Korean population. A meta-analysis of genome-wide association results in two independent Korean cohorts identified 19 RA loci including 6 novel and 13 known loci. The minus log10-transformed association p values for the variants were plotted against their chromosomal positions. Novel and known RA-associated loci exceeding the genome-wide significance threshold (indicated by a red vertical line) are displayed with locus names in red and black, respectively. RA, rheumatoid arthritis.

Figure 2
Figure 2

Regional association plots for novel RA-associated loci. Regional association plots for the six new RA loci: (A) SLAMF6, (B) CXCL13, (C) SWAP70, (D) NFKBIA, (E) ZFP36L1 and (F) LINC00158, represent the minus log10-transformed p values for variants in each locus according to their genomic positions. The lead variants are indicated by purple points and the other variants are coloured according to r2 values with the lead variant in each locus. The names of lead variants and their closest genes are given on the top of the plots. RA, rheumatoid arthritis.

Figure 3
Figure 3

Tissue-specific gene expression in RA loci including the SLAMF6 locus. (A) Tissue-specific gene expression levels in 54 GTEx tissues were analysed by MAGMA to identify tissue-specific expression of RA-associated genes. Five significant tissues (spleen, EBV-transformed lymphocytes, whole blood, lung and small intestine) are highlighted in red bars. The dashed line represents the Bonferroni-corrected significance threshold (=0.05/54). (B) Tissue-specific enrichment of RA variants within histone marks was analysed by GREGOR using Roadmap Epigenomics Project data. FDR-corrected p values for the overlap between RA-risk variants in 19 RA loci and 4 tissue-specific histone marks in 9 tissues were plotted with asterisks indicating significant enrichments with three transcription-activating histone marks in 5 tissues at the FDR threshold of 5% (represented by a dashed line). (C) The Circos plot for the SLAMF6 locus summarises the physical location (blue) with RA-risk variants and chromatin interaction (orange loops) involving both the RA-risk variant and the tissue-specific regulatory regions (including promoters and enhancers) in the five identified tissues. The outer layer in the Circos plot represents the minus log10-transformed RA association p values of variants according to the chromosomal position. The SLAMF6 variant (rs148363003) had chromatin interactions with 12 other coding genes (ARHGAP30, CD48, CD84, IGSF8, ITLN1, KCNJ10, LY9, PEA15, SLAMF1, SLAMF7, TSTD1 and USF1) on chromosome 1. (D) The heat map of gene expression levels represents the predominant expression levels of 11 prioritised RA-relevant RA genes in the 5 identified tissues (indicated by red tissue names and black box lines) among 54 tissues. The 11 RA genes that clustered in a gene expression analysis include known RA-associated genes and SLAMF genes (SLAMF6, LY9, SLAMF1, SLAMF7, CD48 and CD84). EBV, Epstein-Barr virus; RA, rheumatoid arthritis.

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