Bipolar disorder is a common psychiatric illness with devastating consequences for affected individuals, their families, and society. The exact causes of this illness are presently not known, despite considerable research effort dedicated to this objective, in part due to the complexity of the illness, both in its phenotypes and its etiology. Due to this complexity, and although twin and adoption studies clearly demonstrate that bipolar disorder is highly heritable, risk-gene- identification efforts for this illness have been hampered by low power. Research into the biological basis of bipolar disorder is currently advancing in humans and--to a lesser extent--in animals, more or less independently. Each independent line of investigation (i.e., animal and human studies) is contributing to the incremental gains in knowledge of bipolar disorder etiology witnessed in the last decade. Yet, it is now clear that the lack of integration between these two lines of investigation is hindering the pace of risk-gene identification or, perhaps more accurately, constitutes a missed opportunity for optimizing the approach to gene discovery. Our group has laid the foundation for overcoming this barrier to resolving the genetic etiology of bipolar disorder by implementing a convergent functional genomics approach that capitalizes on multiple sources of information from various disciplines to narrow the search for bipolar disorder susceptibility loci and genes, and increase the stringency and accuracy of designating a candidate gene as a causal factor in the illness. In the present application, we propose to apply this methodology to the study of distinct features of the bipolar disorder phenotype (e.g., cycling and switching), and extend it by testing novel candidate genes for association with the illness in a phenotypically enriched and presumably more homogeneous--sample of patients with pediatric onset of bipolar disorder. The goal of this work is to identify the genes that contribute to the emergence of bipolar disorder and regulate its most prominent features: mood cyclicity and switching. The identification of these genes may have numerous consequences for the future of bipolar disorder, including the improvement of diagnostic approaches to the illness, the construction of individually tailored pharmacological and psychosocial treatments for and interventions in the progression of the illness, and, ultimately, the prevention of its occurrence.
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