Schizophrenia (SC) is a severe mental illness that appears to be caused in part by multiple susceptibility genes, each of small effect. Detection of SC susceptibility genes will thus likely require investigation of a very large sample of pedigrees with multiple affected cases and a focus on more genetically homogeneous populations. In response to RFA MH-99-005, we will collect, over three years, diagnostic information and DNA samples from 333 families of Latino descent, each with a minimum of two siblings affected with SC (DSM-IV diagnosis) in order to detect SC susceptibility loci in this population. We have formed a collaboration of seven sites throughout the Southwest United States, Mexico and Central America to accomplish this task. Each site has professional access to a large Latino population and extensive experience in diagnosis of SC in Latinos. Each center will use an opportunistic recruiting mechanism to ascertain probands and families, including sources such as mental health clinics, hospitals, and patient support groups. A uniform approach will be used to diagnose subjects, consisting of blinded interviews with the DIGS (Diagnostic Interview for Genetic Studies), collection of pertinent medical records and laboratory tests, and interview with a close relative of each subject. Training in accurate diagnostic assessment using the DIGS will be provided or all sites and quality control methods will be built into the course of the study. A best estimate consensus process will be used to assign final diagnoses and clinical information for each subject will be entered and stored in a centralized database. Blood samples will be obtained from all family members with a diagnosis of SC or other psychotic illness, as well as from both parents and (if parents are not available), two other siblings. Cell cultures will be created and DNA extracted at the NIMH designated Center for Genetic Studies. In year four of this grant, a complete genome screen at an approximate density of 10 centiMorgans will be completed at CIDR (if approved) or at the University of Texas Health Science Center in San Antonio. Subjects affected with SC and their parents will be genotyped using the ABI Prism Linkage Mapping Set Version2, which consists of over 400 fluorescent-labeled PCR primer pairs from the Genethon human linkage map. Linkage analysis based on identification of multipoint allele sharing in SC subjects (as defined by the final best-estimate DSM-IV diagnosis) will be performed at the Southwest Foundation for Biomedical Research (SFBR). Secondary analyses will also be performed, including covariate analysis. Power analyses with the targeted sample size of this project show that this sample has excellent power to detect SC susceptibility loci with even small genetic effect (Sibs = 1.4 to 2.0). By the end of year for of this grant, all pertinent clinical data, genotyping and pedigree data, and diagnostic information will be transferred from our central database at SFBR and will be made available to the scientific community for pertinent research on SC and related illnesses.
