Abstract
There is increasing evidence that heritable variation in gene expression underlies genetic variation in susceptibility to disease. Therefore, a comprehensive understanding of the similarity between relatives for transcript variation is warranted—in particular, dissection of phenotypic variation into additive and non-additive genetic factors and shared environmental effects. We conducted a gene expression study in blood samples of 862 individuals from 312 nuclear families containing MZ or DZ twin pairs using both pedigree and genotype information. From a pedigree analysis we show that the vast majority of genetic variation across 17,994 probes is additive, although non-additive genetic variation is identified for 960 transcripts. For 180 of the 960 transcripts with non-additive genetic variation, we identify expression quantitative trait loci (eQTL) with dominance effects in a sample of 339 unrelated individuals and replicate 31% of these associations in an independent sample of 139 unrelated individuals. Over-dominance was detected and replicated for a trans association between rs12313805 and ETV6, located 4MB apart on chromosome 12. Surprisingly, only 17 probes exhibit significant levels of common environmental effects, suggesting that environmental and lifestyle factors common to a family do not affect expression variation for most transcripts, at least those measured in blood. Consistent with the genetic architecture of common diseases, gene expression is predominantly additive, but a minority of transcripts display non-additive effects.
Highlights
Understanding the nature of genetic variation for complex traits, including disease, is important in human medicine, evolutionary biology and plant and animal breeding
Only 17 probes exhibit significant levels of common environmental effects, suggesting that environmental and lifestyle factors common to a family do not affect expression variation for most transcripts, at least those measured in blood
Expression Quantitative Trait Loci mapping studies have been very successful in identifying SNPs associated with expression levels; little is currently known about the extent of additive and non-additive genetic variance and the role of common environment on gene expression
Summary
Understanding the nature of genetic variation for complex traits, including disease, is important in human medicine, evolutionary biology and plant and animal breeding. Both the nature of complex trait variation, including the importance of nonadditive genetic variation, and its dissection into contributions from individual genetic loci, have been debated for a century [1,2,3,4,5]. Gene expression is an important complex trait because of increasing evidence of its correlation with disease susceptibility [8,9,10,11] It is an ideal model trait for genetic dissection: it can be measured genome-wide using array or sequencing methods so for each sample thousands of expression phenotypes can be obtained and analysed. If gene expression variation is to be utilized more fully to inform on the biological mechanisms leading to disease susceptibility [11], knowledge of the inheritance patterns and resemblance between individuals is clearly important
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