This proposal is in response to RFA 98-010 entitled """"""""Molecular Genetics of Mental Disorders,"""""""" a research initiative based on recommendations of the National Advisory Mental Health Council and the NIMH Genetics Workgroup. The broad objective of the proposed research is to detect and localize susceptibility loci for bipolar and related mood disorders. This goal will be attained through a genome-wide search for linkage between the disease and marker loci in a large sample of multiplex pedigrees. The investigators propose a two-site international project is to collect the pedigree sample. Specifically, it is proposed to (1) collect a sample of 300 pedigrees, including about 400 affected sib pairs with bipolar I disorder and 60 to 75 extended high- density pedigrees; (2) evaluate subjects clinically using the DIGS and FIGS interviews, and obtain best estimate clinical diagnoses based on interview, family history, and medical records; (3) obtain blood samples from subjects informative for linkage analysis, for DNA extraction and creation of cell lines; (4) conduct a 10cM genome scan with 377 microsattelite markers; (5) analyze the clinical and genotypic data for evidence of linkage using various statistical methods; and (6) based on the linkage results, identify candidate genomic regions for further study. About 1,500 subjects will be studied. The investigators will make available to the scientific community the clinical and biological data to facilitate efforts to map and clone the disease genes. Long-term goals will include the identification and characterization of the disease genes using a gamut of molecular techniques; elucidation of gene-environment, interaction, and characterization of cases with linked genes to identify and define homogenous subsets of the disorder. These long-term objectives will be considered in a renewal application. The availability of a unique series of pedigrees, coupled with recent advances in diagnostic procedures, molecular genetics techniques and linkage analysis methods, bode well for unraveling the genetic mechanisms that underlie some forms of bipolar disorder. This, in turn, may have important implications for the etiology, nosology, pathophysiology and, possibly, prevention and treatment of this disorder.
