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

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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.