SNP-to-gene linking strategies reveal contributions of enhancer-related and candidate master-regulator genes to autoimmune disease

We assess contributions to autoimmune disease of genes whose regulation is driven by enhancer regions (enhancer-related) and genes that regulate other genes in trans (candidate master-regulator). We link these genes to SNPs using several SNP-to-gene (S2G) strategies and apply heritability analyses to draw three conclusions about 11 autoimmune/blood-related diseases/traits. First, several characterizations of enhancer-related genes using functional genomics data are informative for autoimmune disease heritability after conditioning on a broad set of regulatory annotations. Second, candidate master-regulator genes defined using trans-eQTL in blood are also conditionally informative for autoimmune disease heritability. Third, integrating enhancer-related and master-regulator gene sets with protein-protein interaction (PPI) network information magnified their disease signal. The resulting PPI-enhancer gene score produced >2-fold stronger heritability signal and >2-fold stronger enrichment for drug targets, compared with the recently proposed enhancer domain score. In each case, functionally informed S2G strategies produced 4.1- to 13-fold stronger disease signals than conventional window-based strategies. [Display omitted] •Enhancer-related and master-regulator genes provide a unique heritability signal•Integration with protein-protein interaction networks further magnifies the signal•The identified specific gene programs are highly enriched for immune drug target genes•Functional SNP-to-gene (ABC, Roadmap, etc.) linking strategies drive the signal Disease risk variants associated with complex traits and diseases predominantly lie in non-coding regulatory regions of the genes, motivating the need to assess the relative importance of genes for disease through the lens of gene regulation. Here, Dey et al. assess contributions to autoimmune disease of enhancer-related genes and candidate master-regulator genes in blood using SNP-to-gene linking strategies.