Adiposity-Dependent Regulatory Effects on Multi-tissue Transcriptomes

被引:22
作者
Glastonbury, Craig A. [1 ]
Vinuela, Ana [1 ,2 ]
Buil, Alfonso [2 ]
Halldorsson, Gisli H. [3 ]
Thorleifsson, Gudmar [3 ]
Helgason, Hannes [3 ,4 ]
Thorsteinsdottir, Unnur [3 ,5 ]
Stefansson, Kari [3 ,5 ]
Dermitzakis, Emmanouil T. [2 ,6 ,7 ]
Spector, Tim D. [1 ]
Small, Kerrin S. [1 ]
机构
[1] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England
[2] Univ Geneva, Sch Med, Det Genet Med & Dev, CH-1211 Geneva, Switzerland
[3] DeCODE Genet, Sturlugata 8, IS-101 Reykjavik, Iceland
[4] Univ Iceland, Sch Engn & Nat Sci, IS-107 Reykjavik, Iceland
[5] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland
[6] Univ Geneva, Inst Genet & Genom Geneva iGE3, CH-1211 Geneva, Switzerland
[7] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland
基金
英国惠康基金; 英国医学研究理事会;
关键词
ENVIRONMENT INTERACTIONS; GENE-EXPRESSION; LIPID STORAGE; CIDEA; INFLAMMATION; MECHANISMS; DISEASE; LOCI;
D O I
10.1016/j.ajhg.2016.07.001
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 x 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 x BMI interactions (top cis interaction: CHURC1, rs7143432, p = 2.0 x 10(-12)) and one variant regulating 53 genes in trans (top trans interaction: ZNF423, rs3851570, p = 8.2 x 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 x 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 x BMI regulatory effects in four tissues.
引用
收藏
页码:567 / 579
页数:13
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