Genomic copy number variation in schizophrenia

Schizophrenia (OMIM 181500) is an incurable and severe psychiatric disorder comprised of three symptom domains (positive symptoms, negative symptoms and cognitive impairments) with a worldwide prevalence of approximately 1%. There is a substantial amount of evidence demonstrating that schizophrenia has a strong genetic component. Broad-sense heritability estimates range from 64-80% and first-degree relatives of schizophrenia patients have 10-fold increased risk of developing the disorder compared to the general population. It is thought that both single nucleotide polymorphisms and copy number variants (CNVs) contribute to the heritability of schizophrenia. This thesis focuses on the role of CNVs in the etiology of schizophrenia. We performed a genome-wide CNV analysis of 166 schizophrenia patients and 52 psychiatrically healthy controls. In our overall CNV analysis we did not find any significant differences between cases and controls across a variety of CNV categories, nor did we find significant differences when CNVs were partitioned by size (small, medium or large). However, we were the first group to consider small CNVs (< 100-500 kb) in a multiple-hit model where we observed that a slightly higher proportion of case subjects had two-or-more conservative CNVs. We defined a CNV as conservative if it met any of the following three criteria: 1) a known deleterious CNV, 2) a CNV > 1 Mb that was novel to the Database of Genomic Variants (DGV) or 3) a CNV < 1 Mb that was novel to the DGV and that overlapped the coding region of a gene of interest. Genes of interest included genes with a previous association with a neuropsychiatric disorder, or genes with high or specific brain expression, or an association with any other neurocognitive or neuropsychiatric disorders. Two of our case subjects who harbored the highest amount of conservative CNVs also shared a 15q11.2 breakpoint 1-2 (BP1-2) deletion which is a compelling candidate risk locus for schizophrenia. We also found that a slightly higher proportion of case subjects harbored clinically significant CNVs