title: 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.
authors: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors: Craig A
authors: CA
authors: Glastonbury
authors: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors: Ana
authors: A
authors: Viñuela
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland.
authors: Alfonso
authors: A
authors: Buil
authors: deCODE Genetics, Sturlugata 8, Reykjavik IS-101, Iceland.
authors: Gisli H
authors: GH
authors: Halldorsson
authors: deCODE Genetics, Sturlugata 8, Reykjavik IS-101, Iceland.
authors: Gudmar
authors: G
authors: Thorleifsson
authors: deCODE Genetics, Sturlugata 8, Reykjavik IS-101, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik 107, Iceland.
authors: Hannes
authors: H
authors: Helgason
authors: deCODE Genetics, Sturlugata 8, Reykjavik IS-101, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
authors: Unnur
authors: U
authors: Thorsteinsdottir
authors: deCODE Genetics, Sturlugata 8, Reykjavik IS-101, Iceland; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
authors: Kari
authors: K
authors: Stefansson
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva 1211, Switzerland; Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, Geneva C1211, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
authors: Emmanouil T
authors: ET
authors: Dermitzakis
authors: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors: Tim D
authors: TD
authors: Spector
authors: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. Electronic address: kerrin.small@kcl.ac.uk.
authors: Kerrin S
authors: KS
authors: Small
mesh_terms: D015502:Absorptiometry, Photon; D050154:Adiposity / Q000235:genetics*; D015992:Body Mass Index; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D066264:Datasets as Topic; D005260:Female; D006801:Humans; D050152:Intra-Abdominal Fat / Q000033:anatomy & histology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011506:Proteins; D017423:Sequence Analysis, RNA; D059467:Transcriptome / Q000235:genetics*; D014427:Twins / Q000235:genetics; D006113:United Kingdom
chemical_list: D004268:DNA-Binding Proteins; D011506:Proteins; C031017:ornithine decarboxylase antizyme