Functional dissection of noncoding variants associated with rheumatoid arthritis.

Abstract

Objectives: Noncoding variants are critical to our understanding of the genetic basis of diseases and disorders such as rheumatoid arthritis (RA). While genome-wide association studies have identified regions of the genome associated with disease, functional studies are still lagging that can identify potentially causative variants.

Methods: In order to functionally fine-map RA-associated variants, we identified variants at enhancers marked in primary activated T helper cells and conducted massively parallel reporter assay in these cells.

Results: We found that combinations of functional variant genotypes are often exclusive to patients with RA. We leveraged 3-dimensional genome architecture and expression quantitative trait loci data to identify target genes of enhancers exhibiting allelic differences in activity. We confirmed enhancer activity and target gene interactions by Clustered Regularly Interpaced Short Palindromic Repeats Cas9 (CRISPR-Cas9) deletion in primary T cells.

Conclusions: The identification of functional enhancer variants suggests possible causal variants, and their target genes reveal known and novel genes as likely drivers of RA, as well as a means for therapeutic intervention.