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Reference: Glastonbury, CA, Viñuela, A, Buil, A et al., (2016). Adiposity-dependent regulatory effects on multi-tissue transcriptomes. American Journal of Human Genetics, 99 (3), 567-579.Citable link to this page:

 

Adiposity-dependent regulatory effects on multi-tissue transcriptomes.

Abstract: Obesity is a global epidemic that is causally associated with a range of diseases, including type 2 diabetes and cardiovascular disease, at the population-level. However, there is marked heterogeneity in obesity-related outcomes among individuals. This might reflect genotype-dependent responses to adiposity. Given that adiposity, measured by BMI, is associated with widespread changes in gene expression and regulatory variants mediate the majority of known complex trait loci, we sought to identify gene-by-BMI (G × BMI) interactions on the regulation of gene expression in a multi-tissue RNA-sequencing (RNA-seq) dataset from the TwinsUK cohort (n = 856). At a false discovery rate of 5%, we identified 16 cis G × BMI interactions (top cis interaction: CHURC1, rs7143432, p = 2.0 × 10(-12)) and one variant regulating 53 genes in trans (top trans interaction: ZNF423, rs3851570, p = 8.2 × 10(-13)), all in adipose tissue. The interactions were adipose-specific and enriched for variants overlapping adipocyte enhancers, and regulated genes were enriched for metabolic and inflammatory processes. We replicated a subset of the interactions in an independent adipose RNA-seq dataset (deCODE genetics, n = 754). We also confirmed the interactions with an alternate measure of obesity, dual-energy X-ray absorptiometry (DXA)-derived visceral-fat-volume measurements, in a subset of TwinsUK individuals (n = 682). The identified G × BMI regulatory effects demonstrate the dynamic nature of gene regulation and reveal a functional mechanism underlying the heterogeneous response to obesity. Additionally, we have provided a web browser allowing interactive exploration of the dataset, including of association between expression, BMI, and G × BMI regulatory effects in four tissues.

Publication status:PublishedPeer Review status:Peer reviewedVersion:Publisher's versionDate of acceptance:2016-07-01 Funder: Medical Research Council   Funder: Seventh Framework Programme   Funder: Wellcome Trust   Funder: National Institute for Health Research   Notes:© 2016 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Bibliographic Details

Publisher: Elsevier

Publisher Website: http://www.sciencedirect.com/

Journal: American Journal of Human Geneticssee more from them

Publication Website: http://www.sciencedirect.com/science/journal/00029297

Volume: 99

Issue: 3

Issue Date: 2016-09

pages:567-579Identifiers

Doi: https://doi.org/10.1016/j.ajhg.2016.07.001

Eissn: 1537-6605

Issn: 0002-9297

Uuid: uuid:5cf10be3-38ae-439f-9964-4c5827f16854

Urn: uri:5cf10be3-38ae-439f-9964-4c5827f16854

Pubs-id: pubs:691942 Item Description

Type: journal-article;

Language: eng

Version: Publisher's versionKeywords: Absorptiometry, Photon Adiposity Body Mass Index Cohort Studies DNA-Binding Proteins Datasets as Topic Female Humans Intra-Abdominal Fat Male Middle Aged Obesity Organ Specificity Polymorphism, Single Nucleotide Sequence Analysis, RNA Transcriptome Twins United Kingdom

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Author: Glastonbury, CA - Oxford, MSD, NDM, Human Genetics Wt Centre - - - Viñuela, A - - - Buil, A - - - Halldorsson, GH - - - Thorleif

Source: https://ora.ox.ac.uk/objects/uuid:5cf10be3-38ae-439f-9964-4c5827f16854



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