Mapping cis- and trans-regulatory effects across multiple tissues in twins

Grundberg, Elin and Small, Kerrin S and Hedman, Åsa K and Nica, Alexandra C and Buil, Alfonso and Keildson, Sarah and Bell, Jordana T and Yang, Tsun-Po and Meduri, Eshwar and Barrett, Amy and Nisbett, James and Sekowska, Magdalena and Wilk, Alicja and Shin, So-Youn and Glass, Daniel and Travers, Mary and Min, Josine L and Ring, Sue and Ho, Karen and Thorleifsson, Gudmar and Kong, Augustine and Thorsteindottir, Unnur and Ainali, Chrysanthi and Dimas, Antigone S and Hassanali, Neelam and Ingle, Catherine and Knowles, David and Krestyaninova, Maria and Lowe, Christopher E and Di Meglio, Paola and Montgomery, Stephen B and Parts, Leopold and Potter, Simon and Surdulescu, Gabriela and Tsaprouni, Loukia and Tsoka, Sophia and Bataille, Veronique and Durbin, Richard and Nestle, Frank O and O'Rahilly, Stephen and Soranzo, Nicole and Lindgren, Cecilia M and Zondervan, Krina T and Ahmadi, Kourosh R and Schadt, Eric E and Stefansson, Kari and Smith, George Davey and McCarthy, Mark I and Deloukas, Panos and Dermitzakis, Emmanouil T and Spector, Tim D (2012) Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nature genetics, 44 (10). pp. 1084-1089. ISSN 1546-1718

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Official URL: http://www.nature.com/ng/journal/v44/n10/full/ng.2...

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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Article

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https://doi.org/10.1038/ng.2394

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