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

被引：578

作者：

Grundberg, Elin ^{[2
,3
]}

Small, Kerrin S. ^{[2
,3
]}

Hedman, Asa K. ^{[1
]}

Nica, Alexandra C. ^{[4
,5
]}

Buil, Alfonso ^{[4
,5
]}

Keildson, Sarah ^{[1
]}

Bell, Jordana T. ^{[1
,3
]}

Yang, Tsun-Po ^{[2
]}

Meduri, Eshwar ^{[2
,3
]}

Barrett, Amy ^{[6
]}

Nisbett, James ^{[2
]}

Sekowska, Magdalena ^{[2
]}

Wilk, Alicja ^{[2
]}

Shin, So-Youn ^{[2
]}

Glass, Daniel ^{[3
]}

Travers, Mary ^{[6
]}

Min, Josine L. ^{[1
]}

Ring, Sue ^{[7
]}

Ho, Karen ^{[7
]}

Thorleifsson, Gudmar ^{[8
]}

Kong, Augustine ^{[8
]}

Thorsteindottir, Unnur ^{[8
,9
]}

Ainali, Chrysanthi ^{[10
]}

Dimas, Antigone S. ^{[4
,5
]}

Hassanali, Neelam ^{[6
]}

Ingle, Catherine ^{[2
]}

Knowles, David ^{[11
]}

Krestyaninova, Maria ^{[12
]}

Lowe, Christopher E. ^{[13
,14
]}

Di Meglio, Paola ^{[15
]}

Montgomery, Stephen B. ^{[4
,5
]}

Parts, Leopold ^{[2
]}

Potter, Simon ^{[2
]}

Surdulescu, Gabriela ^{[3
]}

Tsaprouni, Loukia ^{[2
]}

Tsoka, Sophia ^{[10
]}

Bataille, Veronique ^{[3
]}

Durbin, Richard ^{[2
]}

Nestle, Frank O. ^{[15
]}

O'Rahilly, Stephen ^{[13
,14
]}

Soranzo, Nicole ^{[2
]}

Lindgren, Cecilia M. ^{[1
]}

Zondervan, Krina T. ^{[1
]}

Ahmadi, Kourosh R. ^{[3
]}

Schadt, Eric E. ^{[16
]}

Stefansson, Kari ^{[8
,9
]}

Smith, George Davey ^{[7
]}

McCarthy, Mark I. ^{[1
,6
,17
]}

Deloukas, Panos ^{[2
]}

Dermitzakis, Emmanouil T. ^{[4
,5
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[2] Wellcome Trust Sanger Inst, Hinxton, England

[3] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England

[4] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

[5] Univ Geneva, Inst Genet & Genom Geneva, Geneva, Switzerland

[6] Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[7] Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol CAiTE, Sch Social & Community Med, Bristol, Avon, England

[8] deCODE Genet, Reykjavik, Iceland

[9] Univ Iceland, Fac Med, Reykjavik, Iceland

[10] Kings Coll London, Dept Informat, Sch Nat & Math Sci, London WC2R 2LS, England

[11] Univ Cambridge, Dept Engn, Cambridge CB2 1PZ, England

[12] European Bioinformat Inst, Hinxton, England

[13] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England

[14] Addenbrookes Hosp, Cambridge Natl Inst Hlth Res NIHR, Biomed Res Ctr, Cambridge, England

[15] Kings Coll London, St Johns Inst Dermatol, London WC2R 2LS, England

[16] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA

[17] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England

来源：

NATURE GENETICS | 2012年 / 44卷 / 10期

基金：

美国国家卫生研究院; 瑞士国家科学基金会; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; GENE-EXPRESSION; DETERMINANTS; VARIANTS; SEQUENCE; SKIN;

D O I：

10.1038/ng.2394

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1084 / +

页数：8

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