Patterns of Cis Regulatory Variation in Diverse Human Populations

Abstract

The genetic basis of gene expression variation has long been studied with the aim to understand the landscape of regulatory variants, but also more recently to assist in the interpretation and elucidation of disease signals. To date, many studies have looked in specific tissues and population-based samples, but there has been limited assessment of the degree of inter-population variability in regulatory variation. We analyzed genome-wide gene expression in lymphoblastoid cell lines from a total of 726 individuals from 8 global populations from the HapMap3 project and correlated gene expression levels with HapMap3 SNPs located in cis to the genes. We describe the influence of ancestry on gene expression levels within and between these diverse human populations and uncover a non-negligible impact on global patterns of gene expression. We further dissect the specific functional pathways differentiated between populations. We also identify 5,691 expression quantitative trait loci (eQTLs) after controlling for both non-genetic factors and population admixture and observe that half of the cis-eQTLs are replicated in one or more of the populations. We highlight patterns of eQTL-sharing between populations, which are partially determined by population genetic relatedness, and discover significant sharing of eQTL effects between Asians, European-admixed, and African subpopulations. Specifically, we observe that both the effect size and the direction of effect for eQTLs are highly conserved across populations. We observe an increasing proximity of eQTLs toward the transcription start site as sharing of eQTLs among populations increases, highlighting that variants close to TSS have stronger effects and therefore are more likely to be detected across a wider panel of populations. Together these results offer a unique picture and resource of the degree of differentiation among human populations in functional regulatory variation and provide an estimate for the transferability of complex trait variants across populations.

Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits

“…11 In contrast to cis-eQTLs, analysis of trans-eQTLs is vastly more computationally challenging and reported trans-eQTLs have proven to be less replicable across studies. 11,12 Therefore, many eQTL studies focus only on cis-eQTLs or a small subset of trans-eQTLs. 12,13 trans-eQTL hotspots are of particular interest because SNPs linked to such hotpots could serve important regulatory roles.…”

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

“…The eQTL analysis using "eQTL resources @ the pritchard lab" was conducted using RNAseq data from a study using total RNA from lymphoblastoid cell lines in 63 HapMap individuals of European ancestry ). The eQTL analysis using Genevar was conducted using expression data from the total RNA of 109 lymphoblastoid cell lines of European ancestry (Stranger et al 2012). The eQTL analysis using SCAN: SNP and CNV annotation database was conducted using expression data from total RNA from lymphoblastoid cell lines of 30 trios of European ancestry and 30 trios of African ancestry (Duan et al 2008), though based on our population, only significant results from the population of European ancestry are included.…”

The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus

“…To identify SNPs associated with changes in expression (ciseQTLs) of ERBB3, we integrated data from multiple eQTL studies (Stranger et al, 2012;Westra et al, 2013;GTEx Consortium, 2015). GWAS SNPs (p-value 0.01) for T1D were retrieved from T1DGC (Barrett et al, 2009) and linkage disequilibrium (LD) analysis was performed using SNAP (Johnson et al, 2008).…”