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.
Highlights
One of the fundamental questions of human population genetics is the extent to which human populations from around the world differ from one another
We analyzed genome-wide gene expression in human cell lines derived from 726 unrelated individuals representing 8 global populations that have been genetically well-characterized by the International HapMap Project
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
Summary
One of the fundamental questions of human population genetics is the extent to which human populations from around the world differ from one another. While there have been extensive studies of human population differentiation with respect to protein coding variants [1,2], little is known about the degree of population differentiation of regulatory variants, either for those with regulatory effects on nearby genes (cis-eQTLs) or those acting over longer genomic distances (trans-eQTLs). This deficit of knowledge needs to be addressed given that it is likely that: (i) a large number of highfrequency eQTLs exist in human populations; (ii) cis-regulatory
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