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

Elin Grundberg, Kerrin S. Small, Asa K. Hedman, Alexandra C. Nica, Alfonso Buil, Sarah Keildson, Jordana T. Bell, Tsun-Po Yang, Eshwar Meduri, Amy Barrett, James Nisbett, Magdalena Sekowska, Alicja Wilk, So-Youn Shin, Daniel Glass, Mary Travers, Josine L. Min, Susan M Ring, Karen Ho, Gudmar ThorleifssonAugustine Kong, Unnur Thorsteindottir, Chrysanthi Ainali, Antigone S. Dimas, Neelam Hassanali, Catherine Ingle, David Knowles, Maria Krestyaninova, Christopher E. Lowe, Paola Di Meglio, Stephen B. Montgomery, Leopold Parts, Simon Potter, Gabriela Surdulescu, Loukia Tsaprouni, Sophia Tsoka, Veronique Bataille, Richard Durbin, Frank O. Nestle, Stephen O'Rahilly, Nicole Soranzo, Cecilia M. Lindgren, Krina T. Zondervan, Kourosh R. Ahmadi, Eric E. Schadt, Kari Stefansson, George Davey Smith, Mark I. McCarthy*, Panos Deloukas, Emmanouil T. Dermitzakis, Multiple Tissue Human Expression R

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

568 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1084-1089
Number of pages5
JournalNature Genetics
Issue number10
Publication statusPublished - Oct 2012


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