Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits

Abstract

DNA variants (SNPs) that predispose to common traits often localize within noncoding regulatory elements such as enhancers. Moreover, loci identified by genome-wide association studies (GWAS) often contain multiple SNPs in linkage disequilibrium (LD), any of which may be causal. Thus, determining the effect of these multiple variant SNPs on target transcript levels has been a major challenge. Here, we provide evidence that for six common autoimmune disorders (rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, lupus, and ulcerative colitis), the GWAS association arises from multiple polymorphisms in LD that map to clusters of enhancer elements active in the same cell type. This finding suggests a "multiple enhancer variant" hypothesis for common traits, where several variants in LD impact multiple enhancers and cooperatively affect gene expression. Using a novel method to delineate enhancer-gene interactions, we show that multiple enhancer variants within a given locus typically target the same gene. Using available data from HapMap and B lymphoblasts as a model system, we provide evidence at numerous loci that multiple enhancer variants cooperatively contribute to altered expression of their gene targets. The effects on target transcript levels tend to be modest and can be either gain- or loss-of-function. Additionally, the genes associated with multiple enhancer variants encode proteins that are often functionally related and enriched in common pathways. Overall, the multiple enhancer variant hypothesis offers a new paradigm by which noncoding variants can confer susceptibility to common traits.

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

“…We are just beginning to understand the functional basis underlying the rs965513 risk in PTC. Similar scenarios are known from GWAS studies of several cancers and other phenotypes (27).…”

“…Multiple enhancer elements were identified within the cancerassociated regions in 8q24; these enhancers regulate Myc promoter activity through a long-range looping mechanism (37). Recently, it was reported that for six common autoimmune disorders (rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, lupus, and ulcerative colitis), the association detected by GWAS was due to multiple polymorphisms in LD that map to clusters of enhancer elements active in the same cell type (27). The authors observed that multiple enhancer variants within a given locus typically target the same gene and that multiple enhancer variants cooperatively contribute to altered expression of their target gene (27).…”

“…Recently, it was reported that for six common autoimmune disorders (rheumatoid arthritis, Crohn's disease, celiac disease, multiple sclerosis, lupus, and ulcerative colitis), the association detected by GWAS was due to multiple polymorphisms in LD that map to clusters of enhancer elements active in the same cell type (27). The authors observed that multiple enhancer variants within a given locus typically target the same gene and that multiple enhancer variants cooperatively contribute to altered expression of their target gene (27). Our data are consistent with this concept and provide further evidence for a "multiple enhancer variants" hypothesis by which noncoding variants can confer susceptibility to common traits.…”

Identification of Novel Genetic Markers of Breast Cancer Survival

“…Expression of neither of the genes near rs148760487 was associated with relapse. Both the two top SNPs lie in putative enhancer sequences for which promoter interactions have been predicted (Supplementary Figure 9, available online) (37,38). IFIH or FAP might be the target of rs148760487, and EI24 might be the target of rs2059614 because the SNP is in an enhancer in endothelial cells that is predicted to regulate EI24.…”

Local Joint Testing Improves Power and Identifies Hidden Heritability in Association Studies

“…In this work we investigate a local joint-testing approach to analysis of genetic data sets in which pairs of variants from the same locus are examined simultaneously for association with a phenotype. The motivation for our approach comes from the mounting evidence that complex traits are highly polygenic (Visscher et al 2012), that causal variants are not evenly distributed across the genome (Gusev et al 2013), that known associated loci often harbor multiple causal variants (Udler et al 2009;Fellay et al 2010;Trynka et al 2011;Wood et al 2011;Liu et al 2012;Patsopoulos et al 2013;Pickrell 2014), and that the underlying causal variants can be in linkage disequilibrium (LD) with each other (Corradin et al 2014).…”