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Mapping cis- and trans-regulatory effects across multiple tissues in twins
Open accessAbstract
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 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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Metadata
- 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
- ORCID
- Grundberg, Elin
- Small, Kerrin S
- Hedman, Åsa K
- Buil, Alfonso
- Bell, Jordana T
- Yang, Tsun-Po
- Meduri, Eshwar
- Sekowska, Magdalena
- Shin, So-Youn
- Glass, Daniel
- Min, Josine L
- Ho, Karen
- Kong, Augustine
- Ainali, Chrysanthi
- Dimas, Antigone S
- Knowles, David
- Krestyaninova, Maria
- Lowe, Christopher E
- Montgomery, Stephen B
- Parts, Leopold
- Tsaprouni, Loukia
- Tsoka, Sophia
- Bataille, Veronique
- Durbin, Richard
- Nestle, Frank O
- Soranzo, Nicole
- Lindgren, Cecilia M
- Zondervan, Krina T
- Ahmadi, Kourosh R
- Schadt, Eric E
- Smith, George Davey
- 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
- PMC
- PMC3784328
- 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
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- 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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