Dataset Information

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.

SUBMITTER: Glastonbury CA

PROVIDER: S-EPMC5011064 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Adiposity-Dependent Regulatory Effects on Multi-tissue Transcriptomes.

Glastonbury Craig A CA Viñuela Ana A Buil Alfonso A Halldorsson Gisli H GH Thorleifsson Gudmar G Helgason Hannes H Thorsteinsdottir Unnur U Stefansson Kari K Dermitzakis Emmanouil T ET Spector Tim D TD Small Kerrin S KS

American journal of human genetics 20160901 3

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 identif ...[more]

PMID: 27588447

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Project description:BackgroundFindings from Mendelian randomization (MR) studies are conventionally interpreted as lifelong effects, which typically do not provide insight into the molecular mechanisms underlying the effect of an exposure on an outcome. In this study, we apply two recently developed MR approaches (known as 'lifecourse' and 'tissue-partitioned' MR) to investigate lifestage-specific effects and tissues of action in the relationship between adiposity and circulating leptin levels.MethodsGenetic instruments for childhood and adult adiposity were incorporated into a multivariable MR (MVMR) framework to estimate lifestage-specific effects on leptin levels measured during early life (mean age: 10 y) in the Avon Longitudinal Study of Parents and Children and in adulthood (mean age: 55 y) using summary-level data from the deCODE Health study. This was followed by partitioning body mass index (BMI) instruments into those whose effects are putatively mediated by gene expression in either subcutaneous adipose or brain tissues, followed by using MVMR to simultaneously estimate their separate effects on childhood and adult leptin levels.ResultsThere was strong evidence that childhood adiposity has a direct effect on leptin levels at age 10 y in the lifecourse (β = 1.10 SD change in leptin levels, 95% CI = 0.90-1.30, p=6 × 10-28), whereas evidence of an indirect effect was found on adulthood leptin along the causal pathway involving adulthood body size (β = 0.74, 95% CI = 0.62-0.86, p=1 × 10-33). Tissue-partitioned MR analyses provided evidence to suggest that BMI exerts its effect on leptin levels during both childhood and adulthood via brain tissue-mediated pathways (β = 0.79, 95% CI = 0.22-1.36, p=6 × 10-3 and β = 0.51, 95% CI = 0.32-0.69, p=1 × 10-7, respectively).ConclusionsOur findings demonstrate the use of lifecourse MR to disentangle direct and indirect effects of early-life exposures on time-varying complex outcomes. Furthermore, by integrating tissue-specific data, we highlight the etiological importance of appetite regulation in the effect of adiposity on leptin levels.FundingThis work was supported by the Integrative Epidemiology Unit, which receives funding from the UK Medical Research Council and the University of Bristol (MC_UU_00011/1).

Dataset Information

Adiposity-Dependent Regulatory Effects on Multi-tissue Transcriptomes.

Publications

Adiposity-Dependent Regulatory Effects on Multi-tissue Transcriptomes.

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