Investigating the Role of Genomic Copy Number Variation in Risk for Schizophrenia

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DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a severe psychiatric disorder with a strong genetic influence on susceptibility. Intense efforts using both linkage and association studies to identify susceptibility loci thus far have met only limited success. Recently it has been appreciated that widespread copy number variation (CNV), in the form of duplications and deletions, frequently occurs in the human genome and is a largely unsurveyed source of individual genetic variation. This study is designed to investigate the hypothesis that CNV may be an unrecognized cause of SZ genetic susceptibility. To accomplish this, we will use an Ashkenazi Jewish population to limit genetic heterogeneity. We will first characterize the distribution of CNV in 500 Ashkenazi Jewish controls, by interrogating the entire nonrepetitive human genome with 2.1 million feature oligonucleotide arrays (average density 1.5 kb) and a competitive genomic hybridization protocol. We expect to identify ~2,000 nonredundant CNVs, large (>100 kb) and small (-15 - 100 kb), frequent (> 1%) and rare (< 1%). We will confirm selected CNV from each of these four classes by an alternate technology, such as quantitative TaqMan PCR or by FISH to metaphase chromosomes. Using prior high-density SNP genotyping in four genomic regions in these samples, we will investigate linkage disequilibrium patterns between individual CNVs and flanking SNPs. Next, we will characterize whole-genome CNV in 500 AJ SZ cases as well as 600 parents of these cases. For common (>1% frequency CNV), these data will be evaluated by joint analysis of trios, cases, and controls for statistically significant evidence of association of one or more CNV loci with SZ. The presence of rare (< 1%) CNV in SZ cases will be evaluated in previously identified linkage regions as well as in or near glutamate gene regions. Significant CNV loci will be carefully scrutinized for their proximity to genes or evolutionarily conserved sequences. This study will result in a detailed examination of CNV in the Ashkenazim, providing one of the first large-scale evaluations of CNV in humans, and identify CNV loci that may influence SZ susceptibility. Schizophrenia is a severe psychiatric disorder that affects 1% of the general population, but causes of this disorder remain unknown. We propose to investigate whether deletions or duplications in the human genome are related to schizophrenia susceptibility; these variants may harbor important clues about the genes, and ultimately the biological process, involved in development of schizophrenia.