Wellcome Trust Sanger Institute, Hinxton, UK.
Nat Genet. 2012 Oct;44(10):1084-9. doi: 10.1038/ng.2394. Epub 2012 Sep 2.
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.
基于序列的基因表达变化是疾病风险的关键驱动因素。在许多表达数量性状基因座 (eQTL) 研究中，已经在许多组织中定位了调节顺式表达的常见变体，通常是在无关个体的单一组织中。在这里，我们对大量单卵和双卵双胞胎的多种组织中的基因表达进行了全面分析，这使得对基因表达的遗传（顺式和反式）和非遗传效应进行系统剖析成为可能。使用血缘关系估计，我们表明，表达的总可遗传顺式效应中至少有 40%不能用常见的顺式变体来解释，这一发现揭示了低频和罕见调节变体在转录调控和复杂性状易感性方面的贡献。我们表明，相当一部分基因表达的遗传性是结构基因的反式遗传，我们鉴定了几个复制的反式变体，它们主要以组织受限的方式起作用，可能调节许多基因的转录。
