The successful identification of calpain-10 and NOD2 as susceptibility genes in diabetes and inflammatory bowel disease in the past year have set powerful precedents for common disease genetics, favoring a strategy for disease gene detection where linkage is detected and followed up by linkage disequilibrium studies within the region. Bipolar disorder (BP) is a common disease (lifetime population prevalence 1 percent) with a complex inheritance pattern. Multiple linkage studies on families with BP have been reported, with intermittently positive results in several regions of the human genome. Meta-analysis of all published whole-genome scans of BP is a rational method for detecting the most promising regions for positional cloning; our meta-analysis found significant linkage in only two regions, 13q32 and 22q11. Chromosome 13q32 is a region that shows linkage to both BP and Schizophrenia; characterization of the region is needed for positional cloning studies in both disorders. Starting with the Human Genome Project and Celera maps, we have recently developed a complete physical map of the 13q32 region, closing all existing gaps in the published maps. We propose here a complete molecular characterization of the 13q32 region, as a framework for identification of a susceptibility variant for BP. We are creating a high density SNP map specific for 13q32-q33, supported by software we are developing. To enrich our SNP database for uncommon SNPs and functionally interesting variants with a potential for susceptibility to BP illness, 7 BP individuals from families with positive linkage scores on 13q32, and 3 control individuals, will have mutational analysis of every gene and EST known in the region. Association studies with parental controls will be done, at an average density of 1/20 kb, on DNA from 196 singletons or affected-sib-pairs of BP patients with 2 genotyped parents, and additional unrelated BPs. These samples are taken from linkage series with suggestive or slightly positive linkage statistics on 13q. Statistical analyses will include single locus and haplotype analyses, partition of linkage evidence, decay of haplotype sharing, and other analyses. Further analysis of positive disequilibrium results will include additional genotyping and haplotyping to corroborate the result, and testing for clinical endophenotypes associated with disease.
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