Modeling disease risk through analysis of physical interactions between genetic variants within chromatin regulatory circuitry

SNPs associated with disease susceptibility often reside in clusters of gene enhancers, or super enhancers. Constituents of these enhancer clusters cooperate to regulate target genes, and often extend beyond the linkage disequilibrium blocks containing GWAS risk SNPs. We identified “outside variants”, defined as SNPs in weak LD with GWAS risk SNPs that physically interact with risk SNPs as part of the target gene’s regulatory circuitry. These outside variants explain additional target gene expression variation beyond that of GWAS associated SNPs. Additionally, the clinical risk associated with the GWAS SNPs is considerably modified by the genotype of the outside variant. Collectively, these findings suggest a potential model whereby outside variants and GWAS SNPs that physically interact in 3D chromatin collude to influence target transcript levels as well as clinical risk. This model offers an additional hypothesis for the source of missing heritability of complex traits.