Heritability and Tissue Specificity of Expression Quantitative Trait Loci

Abstract

Variation in gene expression is heritable and has been mapped to the genome in humans and model organisms as expression quantitative trait loci (eQTLs). We applied integrated genome-wide expression profiling and linkage analysis to the regulation of gene expression in fat, kidney, adrenal, and heart tissues using the BXH/HXB panel of rat recombinant inbred strains. Here, we report the influence of heritability and allelic effect of the quantitative trait locus on detection of cis- and trans-acting eQTLs and discuss how these factors operate in a tissue-specific context. We identified several hundred major eQTLs in each tissue and found that cis-acting eQTLs are highly heritable and easier to detect than trans-eQTLs. The proportion of heritable expression traits was similar in all tissues; however, heritability alone was not a reliable predictor of whether an eQTL will be detected. We empirically show how the use of heritability as a filter reduces the ability to discover trans-eQTLs, particularly for eQTLs with small effects. Only 3% of cis- and trans-eQTLs exhibited large allelic effects, explaining more than 40% of the phenotypic variance, suggestive of a highly polygenic control of gene expression. Power calculations indicated that, across tissues, minor differences in genetic effects are expected to have a significant impact on detection of trans-eQTLs. Trans-eQTLs generally show smaller effects than cis-eQTLs and have a higher false discovery rate, particularly in more heterogeneous tissues, suggesting that small biological variability, likely relating to tissue composition, may influence detection of trans-eQTLs in this system. We delineate the effects of genetic architecture on variation in gene expression and show the sensitivity of this experimental design to tissue sampling variability in large-scale eQTL studies. The combined application of genome-wide expression profiling from microarray experiments with genetic linkage analysis enables the mapping of expression quantitative trait loci (eQTLs), which are primary control points for gene expression across the genome. This approach has been called “genetical genomics”, and recent technological and methodological advances have made its large-scale application feasible in humans and model organisms. Using this approach, the authors have carried out an extensive analysis of the genetic architecture underlying variation in gene expression using a panel of 30 rat recombinant inbred strains. The results are used to explore the relationship between heritability of gene expression, cis- and trans-acting genetic effects, tissue heterogeneity, and statistical cut-offs of significance, which are important factors for large-scale eQTL studies. By examining large eQTL data from four tissues, the authors provide a detailed picture of cis- and trans-eQTL features that may help understanding of the genetic regulation of transcription on a genomic scale. The results also show the sensitivity of this approach to discriminate between cis and trans regulation and the value of the rat system in studying large eQTL datasets from multiple tissues.