Epidemiologic and clinical studies have established that Major Depression (MD) often co-occurs with medical conditions in later life, including metabolic disorders such as Type 2 Diabetes Mellitus (hereafter referred to as 'Diabetes'). It is now acknowledged that the inter-relationship between MD and Diabetes is likely bi-directional. Indeed, there is consistent evidence from population-based cohort studies that MD is associated with increased risk of and mortality from Diabetes and cardiovascular disease. However, prospective studies cannot definitively distinguish whether MD is a unique risk factor for metabolic disorders, or if this phenomenon is due to a common factor shared by both MD and Diabetes such as genetic liability, environmental stress, or systemic physiologic deregulation. Functional genomics, particularly assessment of gene expression, offer a novel means of specifying how environmental exposures intersect with genetic liability to influence physiology. The broad objective of this Career Development Award (K01) is to investigate the etiologic relationships between co-occurring MD and Diabetes, in particular the structural and relative contributions of genetic and environmental sources of risk. This research utilizes complementary approaches to investigating the aims below: first, the broad genetic and environmental pathways underlying this comorbidity will be examined using latent variable twin modeling; second, gene expression arrays will be used to examine specific biological pathways by which depressive symptoms influence Diabetes risk. The specific aims of the research plan are to: 1) evaluate environmental and genetic contributions, and their interaction, of the relationship between MD and Diabetes in later adulthood; 2) investigate the behavioral pathways linking MD and Diabetes while accounting for shared genetic liability; and 3) examine the relationship between depressive symptoms and expression of immune-related genes. The candidate will receive training in responsible conduct of research, genetic epidemiology, and functional genomics. The candidate proposes to implement this research plan during a period of closely mentored training with experts in psychiatry, immunology, functional genomics, epidemiology, and biostatistics. The proposed training plan will promote her transition to independence as an epidemiologist focused on exploring an integrative model of the psychological, behavioral, biological, and genetic aspects of mental health. The research plan addresses the intersection of two common and debilitating health conditions, Major Depression and Diabetes, that are leading sources of healthcare costs and public health burden in the US and globally. The public health significance of this research centers on understanding the etiologic relationships between mental and physical health in order to develop comprehensive programs to improve the health of persons with psychiatric disorders. PUBLIC HEALTH RELEVANCE: The goal of this application is to investigate the etiologic nature of co-occurring MD and Diabetes using complementary data from two population-based cohorts and a genetically informative twin study. The aims are to: 1) evaluate environmental and genetic contributions, and their interaction, of the relationship between MD and Diabetes in later adulthood; 2) investigate the behavioral pathways linking MD and Diabetes while accounting for shared genetic liability; and 3) examine the influence of depressive symptoms on expression of immune-related genes. The significance of this research centers on understanding the etiologic relationships between mental and physical health to improve the health of persons with psychiatric disorders.