Our principal objective is to identify genetic variation that underlies liability to schizophrenia and other psychotic disorders (henceforth called Scz) in the Oceanic population of Palau. We will accomplish this goal by capitalizing on a wide range of scientific expertise and an incredible population sample obtained by enduring relationship between the investigators and the Government of Palau for more than a decade. We now have genealogical information on many thousand individuals, who form a compelling resource for genome-wide linkage and association mapping, and represents complete ascertainment from the Oceanic population of Palau. We propose a genome-wide study of linkage and association for risk to Scz by genotyping 500 individuals for 250,000 Single Nucleotide Polymorphisms (SNPs), using the Affymetrix chip technology. We use these genotypes to search for variation conforming to the conventional hypothesis - that risk to Scz is determined directly by genetic variation carried by affected individuals. We will also use these data to test a novel hypothesis - that initial liability to Scz is generated during fetal development by one or more environmental stressors, but it is facilitated by maternal genetic vulnerability to the stress, so that the placental environment cannot adequately buffer the developing fetus. To effectively search for variation affecting risk at either level (maternal or individual), we propose to genotype essentially all individuals affected by Scz, 250, 150 mothers of individuals diagnosed with Scz, and 100 control individuals. DMA from another 450 individual will be used for follow-up analyses. A rich set of risk maternal risk factors will be collected for this population and used in our analyses. Statistical analyses will target identification of extended haplotypes that are shared much more frequently than expected by chance (in either level of risk.) Identification of such haplotypes will be facilitated by extended linkage disequilibrium characteristic of this and other Oceanic populations. Molecular and fine-mapping studies will identify risk loci. We believe this study is unique among studies of Scz genetics for its population, sample, the research team and the novelty of hypotheses and approach.
