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重要细胞表型。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是一种富有成效的策略，可以揭示常见疾病的潜在机制，既可以识别介导疾病影响的基因和途径，也可以表征疾病相关遗传变异作用的分子机制和组织。以前对基因表达遗传学的研究集中在鉴定调节基因总表达水平的遗传变异。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种方法。在细胞性状如基因表达的背景下，环境可以被解释为对生物体（例如饮食，药物，体育活动或吸烟）或对组织和细胞的生理学（包括肥胖，胰岛素和胆固醇水平）起作用的暴露。本研究将调查环境（生活方式因素和生物医学测量）和遗传学对深度表型组学水平数据集中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具有组织特异性。肥胖是一种世界性流行病，与许多合并症密切相关，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，并不是所有的肥胖个体都会发展出相同的合并症，一些肥胖个体甚至表现出代谢健康。对肥胖相关共病发展过程的不完全了解限制了治疗或预防策略的发展。虽然驱动体重指数（BMI）增加的基因似乎主要在中枢神经系统中起作用，但体内脂肪分布和合并症（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，包括细胞组成，代谢和基因表达有显着影响。因此，肥胖可以掩盖、混淆或改变脂肪组织中遗传变异和基因表达之间的关联。这项研究将考虑肥胖（测量总肥胖和体脂分布）作为一种环境，以确定与肥胖相互作用以调节基因表达的遗传变异。这将允许扩大对肥胖对脂肪细胞的分子效应的理解，并确定可能与肥胖共病的差异发展有关的细胞对肥胖反应的基因型依赖性差异。

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.