This application is to identify heritable, quantitative traits (endophenotypes) that are related to bipolar disorder (BP) and then to use these endophenotypes for linkage and association analyses to identify quantitative trait loci (QTL) in a series of well characterized extended pedigrees. It is hypothesized that the endophenotypes may be more powerfully genetically mapped than the clinical BP phenotype. The first step is to measure selected neuroanatomical, neurocognitive, temperament, and activity related features previously shown or hypothesized to be associated with BP. These features will be measured using high resolution structural magnetic resonance imaging (MRI) brain scans, and widely used scales for neurocognition, temperament, and seasonal/circadian variation in activity. The investigative team has considerable experience in using these assessment tools. Aggregation of each of these features will be assessed in about 400 members of 11 previously investigated extended pedigrees from the genetically isolated populations of Antioquia, Colombia and Costa Rica. These pedigrees were ascertained based on their including multiple individuals affected with severe BP (BP-I). Therefore, these pedigrees should be enriched for the presence of BP-associated alleles for the various endophenotypic features. Any of the endophenotypes that demonstrate familial aggregation will be used for genomewide QTL linkage and association analysis of the complete pedigrees using high-resolution genomewide genotypes (for single nucleotide polymorphisms, SNPs) that we will obtain in this project. The study will take advantage of the well-characterized pedigrees and extensive genealogical and clinical characterization already undertaken by members of the collaborative team on these pedigrees. The genetic homogeneity of the two study populations should enhance the probability that this project will identify QTL associated with BP. Future studies will use the QTL to identify sequence variants that may shed light on the pathophysiology of BP.
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