Objective: Nearly 110 susceptibility loci for rheumatoid arthritis (RA) with modest effect sizes have been identified by population-based genetic association studies, suggesting a large number of undiscovered variants behind a highly polygenic genetic architecture of RA. Here, we performed the largest-ever trans-ancestral meta-analysis with the aim to identify new RA loci and to better understand RA biology underlying genetic associations.

Methods: Genome-wide RA association summary statistics in three large case-control collections consisting of 311,292 individuals of Korean, Japanese, and European populations were used in an inverse-variance-weighted fixed-effects meta-analysis. Several computational analyses using public omics resources were conducted to prioritize causal variants and genes, RA variant-implicating features (tissues, pathways, and transcription factors), and potentially repurposable drugs for RA treatment.

Results: We identified 11 new RA susceptibility loci that explained 6.9% and 1.8% of the SNP-based heritability in East Asians and Europeans, respectively, and confirmed 71 known non-HLA susceptibility loci, identifying 90 independent association signals. The RA variants were preferentially located in binding sites of various transcription factors and in cell type-specific transcription-activation histone marks that simultaneously highlighted the importance of CD4⁺ T-cell activation and the potential role of non-immune organs in RA pathogenesis. A total of 615 plausible effector genes, based on gene-based associations, expression-associated variants, and chromatin interaction, included targets of drugs approved for RA treatments and potentially repurposable drugs approved for other indications.

Conclusion: Our findings provide useful insights regarding RA genetic etiology and variant-driven RA pathogenesis.

The association summary statistics were generated from a genome-wide association study in rheumatoid arthritis using large cohorts of Korean, Japanese, and European populations (311,292 individuals).

Please find detailed information from our research article:

Eunji Ha, Sang-Cheol Bae, and Kwangwoo Kim; "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."; Annals of the Rheumatic Disease; in press.