Multi-ancestral GWAS with the VA Million Veteran Program enables functional interpretation of rheumatoid arthritis alleles

Abstract

Introductory ParagraphRheumatoid arthritis (RA) is a heritable and common autoimmune condition. To date, most genetic associations were derived from individuals with either European or East Asian ancestries. Here, we applied a multimodal automated phenotyping strategy to define RA and performed a genome-wide association study (GWAS) of RA in the Million Veteran Program (MVP), including underrepresented African American (AFR) and Admixed American (AMR) populations. Meta-analyses with previous RA cohorts identified 152 autosomal genome-wide significant loci, of which 31 were novel. Inclusion of multi-ancestry data dramatically improved fine-mapping resolution. Functional characterization of these loci using single-cell transcriptomic and chromatin data suggested new RA genes such as CHD7 and CD247. We identified underappreciated functional roles of fine-grained immune cell states other than T cells, such as B cell and myeloid cell states. We observed that multi-ancestry polygenic risk scores using our data demonstrated better predictive ability, especially for AFR and AMR populations.