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Abstract

Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.

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Figures

Fig 1
Fig 1. Genetic and non-genetic effect of gene expression across multiple tissues
Estimation of the proportion of variation in expressed transcripts in adipose (N=11394), LCL (N=10631) and skin tissue (N=11932) attributable to genetic (narrow-sense heritability, h2)(A) and familial non-genetic factors (shared common environment, CE)(B). The y-axis is showing the proportion of transcripts at h2/CE cut-off indicated on the x-axis.
Fig 2
Fig 2. The contribution of heritable cis-components to gene expression variation
The contribution of individual cis-SNPs (MAF>5%) to the genetic variance of gene expression (h2>0.1) in adipose (A), LCL (B), and skin tissue (C). The x-axis is showing the proportion of the heritability of each transcript that is explained by independent cis-SNPs.
Fig 3
Fig 3. Trans-variants regulating expression of multiple transcripts
(A)P value distributions (x-axis) of genome-wide associations(N, y-axis) between two potential adipose multi-gene regulators (rs1752223 on chromosome 1, upper panel, and rs7595947 on chromosome 2, lower panel) and transcript levels in adipose (left panel), LCL (middle) and skin tissue (right panel). (B) Plots showing the median trans-π1 (π1 calculated from p-value distribution of a trans-SNP vs. all probes) at increasing levels of trans-SNP significance in adipose (left panel), LCL (middle) and skin tissue (right panel). The top trans-SNP for each probe was included and trans-SNPs were divided into non-overlapping bins based on the p value of the top trans- association. The median π1(y-axis) is graphed against the -log p (x-axis) of the lower limit of each bin.
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