Gene by environment interactions in the regulation of gene expression across primary tissues and their application to obesity and related traits

基因表达是受遗传和环境控制的一种重要的细胞表型。基因表达的变化似乎是常见疾病全基因组关联研究中确定的大多数遗传关联的基础。因此，研究基因表达的遗传调控对于揭开常见疾病的潜在机制是一项卓有成效的战略，无论是在确定介导疾病影响的基因和途径方面，还是在表征与疾病相关的遗传变异发挥作用的分子机制和组织方面。以前对基因表达遗传学的研究主要集中在识别调节基因总表达水平的遗传变异上。这项研究将通过纳入环境的影响及其与基因组的相互作用来扩展这一方法。在基因表达等细胞特征的背景下，环境可被解释为对有机体(如饮食、药物、体育活动或吸烟)或组织和细胞的生理(包括肥胖、胰岛素和胆固醇水平)起作用的暴露。这项研究将调查环境(生活方式因素和生物医学测量)和遗传学在一个深表型的‘组学水平数据集’中对基因表达调控的联合影响。重要的是，这项研究包括多种疾病相关组织，因为基因调控和疾病表现都是组织特有的。肥胖是一种世界性的流行病，与许多并存疾病密切相关，包括2型糖尿病、心血管疾病、骨关节炎、某些癌症和死亡率增加。然而，并不是所有的肥胖者都会患上同样的共病，一些肥胖者甚至看起来代谢健康。对肥胖相关共病发生过程的不完全了解限制了治疗或预防策略的发展。虽然导致体重指数(BMI)增加的基因似乎主要作用于中枢神经系统，但导致身体脂肪分布和共病(如胰岛素抵抗和2型糖尿病)的基因在脂肪组织中活跃。肥胖对脂肪组织有很大影响，包括细胞组成、新陈代谢和基因表达。因此，肥胖可以掩盖、混淆或改变脂肪组织中基因变异和基因表达之间的联系。这项研究将肥胖症(以总肥胖度和身体脂肪分布衡量)作为一个环境，以确定与肥胖症相互作用的基因变异，以调节基因表达。这将扩大对肥胖对脂肪细胞的分子影响的理解，并确定肥胖细胞反应中依赖于基因型的差异，这些差异可能与肥胖共病的不同发展有关。

Gene expression is an important cellular phenotype under both genetic and environmental control. Changes in gene expression appear to underlie the majority of genetic associations identified in genome-wide association studies of common disease. Studying the genetic regulation of gene expression has thus been a fruitful strategy to unraveling the underlying mechanisms of common disease, both in identifying the genes and pathways that mediate the effects of disease and in characterizing the molecular mechanisms and tissues by which disease-associated genetic variants act. Previous research into the genetics of gene expression has focused on identifying genetic variants that regulate the total expression level of a gene. This study will expand on this approach by incorporating the effects of the environment and its interactions with the genome. In the context of a cellular trait like gene expression the environment can be interpreted as exposures that operate on the organism (eg diet, medication, physical activity, or smoking) or on the physiology of tissues and cells (including obesity, insulin and cholesterol levels). This study will investigate the joint effects of the environment (lifestyle factors and biomedical measurements) and genetics on the regulation of gene expression in a deeply phenotyped, 'omics level dataset. Importantly, this study includes multiple disease-relevant tissues as both gene regulation and disease manifestation is tissue specific. Obesity is a worldwide epidemic and is robustly associated with many co-morbidities including type 2 diabetes, cardiovascular disease, osteoarthritis, certain cancers and increased mortality. However, not all obese individuals develop the same co-morbidities and some obese individuals even appear to be metabolically healthy. Incomplete knowledge of the processes involved in the development of obesity-associated co-morbidities has limited the development of treatments or prevention strategies. While the genes driving increased body mass index (BMI) appear to act primarily in the Central Nervous System, genes underlying body fat distribution and co-morbidities such as insulin resistance and Type 2 Diabetes are active in fat tissue. Obesity has a dramatic effect on fat tissue, including cell composition, metabolism and gene expression. Obesity can thus mask, confound or modify associations between genetic variants and gene expression in fat tissue. This study will consider obesity (measured both as total adiposity and body fat distribution) as an environment in order to identify genetic variants that interact with obesity to regulate gene expression. This will allow an expanded understanding of the molecular effects of obesity on fat cells and identify genotype-dependent differences in the cellular response to obesity that could be linked to differential development of obesity co-morbidities.