Integrated analysis of genome-wide copy number variation and exome-wide rare variation identified novel loci for rheumatoid arthritis.

Objectives: The genetic underpinnings of RA remain partially elucidated, motivating our exploration of copy number variations (CNV) and rare variations in the pathogenesis of RA.

Methods: We conducted an integrated analysis of the genome-wide landscape of CNV and exome-wide rare variation associations with RA in the UK Biobank. To strengthen our findings, we corroborated the results by the differentially expressed genes identified from gene expression profiles of synovial tissue of RA patients and health controls. Furthermore, we leveraged the Drug-Gene Interaction Database to explore potential drugs that could be repurposed to target genes found to be associated with RA.

Results: After adjusted for the covariates, genome-wide CNV association study identified 92 significant signals and the gene-based burden test of the exonic variants identified 94 genome-wide significant associations for RA. Integrating genome-wide CNV and exome-wide rare variation analysis identified 3 common loci for RA, such as GPER1. Two overlapped genes were detected by CNV findings and gene expression profiles for RA, such as HLA-DQB1. Utilising a gene-drug interaction database, we identified novel pharmacological agents that could modulate the activity of these common genes.

Conclusions: This study provides valuable insights into deciphering the genetic basis of RA and offers potential precision medicine strategies for RA.