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; Sue Ring; Karen Ho; Gudmar Thorleifsson; Augustine 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; Tim D. Spector; Multiple Tissue Human Expression R

doi:10.1038/ng.2394

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, Sue 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, Tim D. Spector, Multiple Tissue Human Expression R

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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.

Original language	English
Pages (from-to)	1084-1089
Number of pages	8
Journal	Nature Genetics
Volume	44
Issue number	10
DOIs	https://doi.org/10.1038/ng.2394
Publication status	Published - Oct 2012

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Grundberg, E., Small, K. S., Hedman, A. K., Nica, A. C., Buil, A., Keildson, S., Bell, J. T., Yang, T.-P., Meduri, E., Barrett, A., Nisbett, J., Sekowska, M., Wilk, A., Shin, S.-Y., Glass, D., Travers, M., Min, J. L., Ring, S., Ho, K., ... Multiple Tissue Human Expression R (2012). Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nature Genetics, 44(10), 1084-1089. https://doi.org/10.1038/ng.2394

@article{d44048a29c654426b66faa65162a64e3,

title = "Mapping cis- and trans-regulatory effects across multiple tissues in twins",

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.",

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

year = "2012",

month = oct,

doi = "10.1038/ng.2394",

language = "English",

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Grundberg, E , Small, KS, Hedman, AK, Nica, AC, Buil, A, Keildson, S, Bell, JT, Yang, T-P, Meduri, E, Barrett, A, Nisbett, J, Sekowska, M, Wilk, A, Shin, S-Y, Glass, D, Travers, M, Min, JL, Ring, S, Ho, K, Thorleifsson, G, Kong, A, Thorsteindottir, U, Ainali, C, Dimas, AS, Hassanali, N, Ingle, C, Knowles, D, Krestyaninova, M, Lowe, CE, Di Meglio, P, Montgomery, SB, Parts, L, Potter, S, Surdulescu, G, Tsaprouni, L, Tsoka, S, Bataille, V, Durbin, R, Nestle, FO, O'Rahilly, S, Soranzo, N, Lindgren, CM, Zondervan, KT, Ahmadi, KR, Schadt, EE, Stefansson, K, Smith, GD, McCarthy, MI, Deloukas, P, Spector, TD & Multiple Tissue Human Expression R 2012, 'Mapping cis- and trans-regulatory effects across multiple tissues in twins', Nature Genetics, vol. 44, no. 10, pp. 1084-1089. https://doi.org/10.1038/ng.2394

TY - JOUR

T1 - Mapping cis- and trans-regulatory effects across multiple tissues in twins

AU - Grundberg, Elin

AU - Small, Kerrin S.

AU - Hedman, Asa K.

AU - Nica, Alexandra C.

AU - Buil, Alfonso

AU - Keildson, Sarah

AU - Bell, Jordana T.

AU - Yang, Tsun-Po

AU - Meduri, Eshwar

AU - Barrett, Amy

AU - Nisbett, James

AU - Sekowska, Magdalena

AU - Wilk, Alicja

AU - Shin, So-Youn

AU - Glass, Daniel

AU - Travers, Mary

AU - Min, Josine L.

AU - Ring, Sue

AU - Ho, Karen

AU - Thorleifsson, Gudmar

AU - Kong, Augustine

AU - Thorsteindottir, Unnur

AU - Ainali, Chrysanthi

AU - Dimas, Antigone S.

AU - Hassanali, Neelam

AU - Ingle, Catherine

AU - Knowles, David

AU - Krestyaninova, Maria

AU - Lowe, Christopher E.

AU - Di Meglio, Paola

AU - Montgomery, Stephen B.

AU - Parts, Leopold

AU - Potter, Simon

AU - Surdulescu, Gabriela

AU - Tsaprouni, Loukia

AU - Tsoka, Sophia

AU - Bataille, Veronique

AU - Durbin, Richard

AU - Nestle, Frank O.

AU - O'Rahilly, Stephen

AU - Soranzo, Nicole

AU - Lindgren, Cecilia M.

AU - Zondervan, Krina T.

AU - Ahmadi, Kourosh R.

AU - Schadt, Eric E.

AU - Stefansson, Kari

AU - Smith, George Davey

AU - McCarthy, Mark I.

AU - Deloukas, Panos

AU - Spector, Tim D.

AU - Multiple Tissue Human Expression R

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

U2 - 10.1038/ng.2394

DO - 10.1038/ng.2394

M3 - Article

SN - 1061-4036

VL - 44

SP - 1084

EP - 1089

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

Abstract

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