High Density Genome Wide Linkage Analysis of 922 Bipolar Families

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DESCRIPTION (provided by applicant): From 1988 to 2003 the NIMH Genetics Initiative supported the ascertainment and banking of 699 multiplex bipolar families. Genome wide linkage analyses of these families have yielded statistically significant evidence for a few disease predisposing loci but in contrast to schizophrenia, gene- mapping studies of bipolar disorder have produced fewer findings. While genome wide association studies will soon come into play, there are a number of compelling reasons to support larger scale linkage studies with additional families and a higher density of DMA markers (-4 cM or less). To date, most linkage studies have averaged only -50 to 250 families and were obviously underpowered. Moreover, genotyping of these families, many of which were sib pairs with missing Barents, was carried out using microsatellites spaced only every -10 cMs. Genetic information content was .6 or less for most studies. Theoretical and empirical data indicate higher density genotyping of a larger sample of families will be worthwhile, especially if focused on one ethnic group. In order to assemble this unique and statistically powerful sample we will first select for analyses the 665 European Caucasian families currently available in the NIMH repository. Second, we will add to this sample 257 additional non-repository European Caucasian families previously collected by Ray Depaulo, Francis McMahon, Jimmy Potash, Eliot Gershon, John Kelsoe, Douglas Blackwood and William Byerley. The 922 families contain 1,840 cases of BPI disorder or SA-BP (4 percent of BPI total), 327 subjects with BPI and 810 individuals with Recurrent Depressive Disorder. All together there are 2,977 affected cases. The Center for Inherited Disease Research (CIDR) has approved genotyping of all 922 families (~6,000 subjects) with the 6K Illumina optical bead array. Power analysis indicates that we have 80 percent power at lod > 3.0 to detect linkage to lambdas of at least 1.2. Parametric and non-parametric linkage analyses will be carried out. Fine mapping studies are proposed for year 2 in one to two linkage regions not previously identified by other groups. All together we estimate that NIMH has invested over $20 million in direct costs just for the collection of these families. The proposed study will fully maximize the NIMH investment.