This is a proposal to perform a genome-wide association study of schizophrenia in a large sample of patients and controls from a single region in The Netherlands. This study will be followed by a replication study in a similar but independent Dutch sample. The goal of the project is to identify unambiguous associations between schizophrenia and sequence variants that are common in most populations of European descent. The study population is exceptional in the uniformity of its ascertainment and the rigor and depth of the phenotyping that has been carried out in it. In addition to assessments for DSM-IV diagnoses, neuroimaging data (from magnetic resonance imaging) are available for a substantial portion of cases and controls; many individuals have been imaged twice. Another feature of this sample is that most patients remain under the care of the same clinicians who enrolled them in the study, permitting unusual opportunities for longitudinal evaluations, including reassessment of clinical characteristics and family-based follow-up studies. The sample will be genotyped using >250,000 haplotype tag single nucleotide polymorphisms (SNPs) identified in the International HapMap project. These SNPs are all informative in a European-descended sample from the HapMap, and are therefore ideally suited for use in the Dutch sample. The genotyping will be performed using a high-throughput bead-chip platform for which the SNPs have been previously optimized. The association study will be performed in stages. Stage I is a genome-wide screen of 250,000 SNPs in an initial Dutch sample. Analyses will include two-point analysis between cases and controls, and haplotype-based methods. Stage II will test, in an independent Dutch sample, those SNPs or haplotypes that showed evidence for association in the genome screen that meet pre-set thresholds for significance. The goal of this strategy is to detect true schizophrenia susceptibility loci while limiting false positive findings to a very small number (< 10 in the genome). Follow-up studies will be initiated to refine disease-associated haplotypes and identify sequence variants that increase the risk for schizophrenia. Further delineation of intermediate schizophrenia phenotypes will be used to study their respective contributions to disease susceptibility loci identified in this study. ? ? ?
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