Cited by 748Genetic Associations and EpidemiologyGenetic Mapping and Diversity in Plants and AnimalsGenomics and Chromatin Dynamics

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

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The Multiple Tissue Human Expression Resource (MuTHER) Consortium, Grundberg, Elin, Small, Kerrin S, Hedman, Åsa K, Nica, Alexandra C, Buil, Alfonso, Keildson, Sarah, Bell, Jordana T +44 more·2012·Nature Genetics

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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  • Previous studies have evaluated the association between genetic variation and transcript expression in humans.

    “Previous studies have evaluated the association between variation and transcript expression in humans (1-3).”

    From Impact of regulatory variation from RNA to protein (2015) · cites this paper as [3]

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Authors
The Multiple Tissue Human Expression Resource (MuTHER) Consortium, Grundberg, E., Small, K. S., Hedman, Å. 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., Thorleifsson, G., Kong, A., Thorsteindottir, U., Ainali, C., Dimas, A. S., Hassanali, N., Ingle, C., Knowles, D., Krestyaninova, M., Lowe, C. E., Di Meglio, P., Montgomery, S. B., Parts, L., Potter, S., Surdulescu, G., Tsaprouni, L., Tsoka, S., Bataille, V., Durbin, R., Nestle, F. O., O'Rahilly, S., Soranzo, N., Lindgren, C. M., Zondervan, K. T., Ahmadi, K. R., Schadt, E. E., Stefansson, K., Smith, G. D., McCarthy, M. I., Deloukas, P., Dermitzakis, E. T., & Spector, T. D.
Affiliations
  • King's College London (GB)
  • Centre for Human Genetics (GB)
  • University of Geneva (CH)
  • Wellcome Sanger Institute (GB)
  • Churchill Hospital (GB)
  • University of Bristol (GB)
  • deCODE Genetics (Iceland) (IS)
  • University of Cambridge (GB)
  • European Bioinformatics Institute (GB)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
  • McCarthy, Mark I
  • Deloukas, Panos
  • Dermitzakis, Emmanouil T
  • Spector, Tim D
Venue
Nature Genetics
Published
2012-09-02
Volume
44
Issue
10
Pages
1084-1089
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W2019232525
Cited by
729
References
44
Citations by year
2026: 8 · 2025: 21 · 2024: 15 · 2023: 26 · 2022: 40 · 2021: 41 · 2020: 47 · 2019: 58 · 2018: 52 · 2017: 87 · 2016: 88 · 2015: 94 · 2014: 86 · 2013: 59 · 2012: 5
FWCI
47.03
Type
journal article
Language
en
Open access
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • Bristol Research (University of Bristol) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
  • BCU Open Access Repository (Birmingham City University) (submittedVersion)
Funders
  • National Science Foundation (FP7/2007-2013)
  • Wellcome Trust (FP7/2007–2013, 095515, 081917/Z/07/Z, 085235, 092731, 090532)
  • Louis-Jeantet Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (FP7/2007-2013, 201413)
  • National Institutes of Health (FP7/2007-2013)
  • National Institute of Mental Health (HEALTH-F4-2007-201413, R01MH090941)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
heritability of gene expression, cis-regulatory effects, monozygotic twins, dizygotic twins, expression quantitative trait loci, identity by descent, low-frequency variants, tissue-specific gene expression
MeSH terms
Adult, Aged, Aged, 80 and over, Chromosome Mapping, Female, Gene Expression Regulation, Humans, Genetic Linkage, Lymphocytes, Middle Aged, Models, Genetic, Organ Specificity, Skin, Transcription, Genetic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Subcutaneous Fat, Gene-Environment Interaction

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