biostudies-literatureDey KKNHGRI NIH HHS100145https://www.ebi.ac.uk/biostudies/studies/S-EPMC9306342biostudies-literatureUnknown2(7)We assess contributions to autoimmune disease of genes whose regulation is driven by enhancer regions (enhancer-related) and genes that regulate other genes in <i>trans</i> (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 <i>trans</i>-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.Cell genomicsSNP-to-gene linking strategies reveal contributions of enhancer-related and candidate master-regulator genes to autoimmune disease.PMC9306342R00 HG009917K99 HG012203R35 HG011324Price ALvan de Geijn BNasser JKim SSDey KKGazal SEngreitz JMfalseSNP-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 <i>trans</i> (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 <i>trans</i>-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.2022-01-01T00:00:00Z2022 Jul2024-11-09T16:10:30.159Z2024-11-09T16:10:30.159ZS-EPMC93063423587367310.1016/j.xgen.2022.100145