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.
Highlights
Obesity (MIM: 601665) is a global epidemic that has been robustly associated with a range of co-morbidities such as cardiovascular disease, insulin resistance, type 2 diabetes (T2D [MIM: 125853]), and increased risk of certain types of cancer.[1,2] at the individual level, co-morbidity development among obese individuals is heterogeneous, suggesting that genetics and adiposity might interact to mediate downstream disease and complex trait development.[3]
We describe the pervasive effect BMI has on peripheral-tissue gene expression and identify robust examples of BMI-dependent regulatory variants
We characterize the properties of G 3 BMI regulatory variants, showing that they typically have strong main effects and are highly tissue specific
Summary
Obesity (MIM: 601665) is a global epidemic that has been robustly associated with a range of co-morbidities such as cardiovascular disease, insulin resistance, type 2 diabetes (T2D [MIM: 125853]), and increased risk of certain types of cancer.[1,2] at the individual level, co-morbidity development among obese individuals is heterogeneous, suggesting that genetics and adiposity might interact to mediate downstream disease and complex trait development.[3]. BMI-associated genetic variants are enriched for hypothalamic processes,[6] which suggests that the variants that cause obesity exert their effects primarily in the brain. Variants for many obesity co-morbid traits are primarily thought to regulate genes active in certain peripheral tissues, such as adipose, muscle, and the liver (insulin resistance),[7] the heart and endothelial cells (QT-interval, which is predictive of cardiovascular disease),[8] and adipose (body-fat distribution ),[9] for example. BMI could influence co-morbidity development by modifying gene expression in relevant peripheral tissues directly or by interacting with regulatory variants active in those tissues
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