Functional Architectures of Local and Distal Regulation of Gene Expression in Multiple Human Tissues

Abstract

Genetic variants that modulate gene expression levels play an important role in the etiology of human diseases and complex traits. Although large-scale eQTL mapping studies routinely identify many local eQTLs, the molecular mechanisms by which genetic variants regulate expression remain unclear, particularly for distal eQTLs, which these studies are not well powered to detect. Here, we leveraged all variants (not just those that pass stringent significance thresholds) to analyze the functional architecture of local and distal regulation of gene expression in 15 human tissues by employing an extension of stratified LD-score regression that produces robust results in simulations. The top enriched functional categories in local regulation of peripheral-blood gene expression included coding regions (11.413), conserved regions (4.673), and four histone marks (p < 5 3 10 À5 for all enrichments); local enrichments were similar across the 15 tissues.We also observed substantial enrichments for distal regulation of peripheral-blood gene expression: coding regions (4.473), conserved regions (4.513), and two histone marks (p < 3 3 10 À7 for all enrichments). Analyses of the genetic correlation of gene expression across tissues confirmed that local regulation of gene expression is largely shared across tissues but that distal regulation is highly tissue specific. Our results elucidate the functional components of the genetic architecture of local and distal regulation of gene expression.

Linkage disequilibrium–dependent architecture of human complex traits shows action of negative selection

“…We also considered functional annotations from a “baseline model” 8,19 including 28 main annotations such as coding, conserved, DHS and histone marks (59 total annotations; see Online Methods).…”

“…The 53 annotations also include 500bp windows around each of the 24 main annotations, 100bp windows around four of the main annotations, and an annotation containing all SNPs. We added four binary annotations based on super enhancers and typical enhancers 53 , as previously described 19 . We also added two conserved annotations based on GERP++ scores 54 , including one continuous annotation based on the neutral rate (NS) score and one binary annotation based on a rejected substitutions (RS) score ≥ 4, as we observed significant effects for these annotations (see Supplementary Table 19).…”

Challenges and progress in interpretation of non-coding genetic variants associated with human disease

“…7 Indeed, meta-analyses showed that eQTLs were gene centric and enriched in both putative regulatory elements and GWAS SNPs, suggesting a possible general model where GWAS variants modulate enhancer function and affect nearby transcribed genes. 63,64 One general concern for QTL studies is the extraordinarily high dimensionality of the data. For example, the total number of parameters is equal to the product of the number of Table 1 Methods for studying the functionality of non-coding GWAS variants.…”

Genetic association of molecular traits: A help to identify causative variants in complex diseases

“…Altogether, these studies revealed important recurrent features of the thousands of eQTLs found in different tissues. Thus, almost 60%‐80% of genes have at least one eQTL, mostly cis ‐acting usually within 1 Mb of the transcription start site (TSS) . Distant eQTLs or even eQTLs lying on a different chromosome are less frequent, although a bias due to a lack of statistical power to detect them cannot be excluded .…”

“…Thus, almost 60%-80% of genes have at least one eQTL, 64 mostly cis-acting usually within 1 Mb of the transcription start site (TSS). 89 Distant eQTLs or even eQTLs lying on a different chromosome are less frequent, although a bias due to a lack of statistical power to detect them cannot be excluded. 90 A general rule is that the more distant the eQTLs, the more cell-and context-specific and the lower their effect sizes.…”