Susceptibility to schizophrenia appears to be transmitted in part through a complex genetic mechanism involving interaction of multiple genes, each of relatively small effect. Detection of such loci through genetic linkage studies is likely to require a very large sample of multiply affected pedigrees. In response to RFA MH-99-005, nine investigators propose a Collaborative Study of Mental Disorders to collect in three years a sample of 517 affected sibling pairs (ASPs) with DSM-IV schizophrenia, to complete a genome scan of these pedigrees for multipoint ASP analysis to detect susceptibility loci, and to share biological materials, genotypes and blinded clinical data with the scientific community through an NIMH-sponsored mechanism. Each site will recruit families in a large geographic area, using an opportunistic ascertainment strategy and efficient assessment procedures to maximize the number of ASPs collected. Subjects suspected of having schizophrenia will be assessed with the Diagnostic Interview for Genetic Studies supplemented by information from the Family interview for Genetic studies and medical records. Diagnoses will be made by consensus best-estimate procedures. Interviewer training and quality assurance monitoring of protocol adherence will be provided for all sites. Blood specimens will be obtained from all individuals with psychotic disorders plus their parents and (when both parents are not available) up to two additional siblings to provide genetic phase information. Permanent cell lines will be created and DNA extracted at the NIMH-sponsored Center for Genetic Studies. All clinical data will be merged regularly into a central study database, and blinded data transmitted to the Center for Genetic Studies. At the end of the four-year project period, biological materials and blinded pedigree and clinical data will be made available to scientific community for genetic studies of schizophrenia and related disorders. In year 4, a genome scan will be undertaken at CIDR (if approved) or at the University of Chicago. Affected subjects and relatives needed for phase information will be genotyped using the latest screening map, currently the Weber Version 9 Linkage Mapping Set, containing 387 microsatellite markers at approximately 10 cM spacing. The primary statistical approach will be multipoint analysis of allele sharing in affected individuals, with DSM-IV schizophrenia defined as affected. Secondary analyses will also be carried out. Power analyses suggest that this study would have excellent power to detect loci associated with lambda sibs of 1.4, and moderate power for a value of 1.3, i.e., loci with relatively small etiologic effects.
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