title: 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.
authors.affiliation: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom. enrico.petretto@csc.mrc.ac.uk
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mangion
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dickens
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
authors.forename: Mande K
authors.initials: MK
authors.lastname: Kumaran
authors.forename: Han
authors.initials: H
authors.lastname: Lu
authors.forename: Judith
authors.initials: J
authors.lastname: Fischer
authors.forename: Henrike
authors.initials: H
authors.lastname: Maatz
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kren
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
mesh_terms: D000483:Alleles; D000818:Animals; D005786:Gene Expression Regulation / Q000235:genetics*; D014644:Genetic Variation; D016678:Genome / Q000235:genetics; D008297:Male; D009928:Organ Specificity; D040641:Quantitative Trait Loci / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D012333:RNA, Messenger