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Investigators have linked rare copy number variation (CNVs) to neuropsychiatric diseases, such as schizophrenia. One hypothesis is that CNV events cause disease by affecting genes with specific brain functions. Under these circumstances, we expect that CNV events in cases should impact brain-function genes more frequently than those events in controls. Previous publications have applied “pathway” analyses to genes within neuropsychiatric case CNVs to show enrichment for brain-functions. While such analyses have been suggestive, they often have not rigorously compared the rates of CNVs impacting genes with brain function in cases to controls, and therefore do not address important confounders such as the large size of brain genes and overall differences in rates and sizes of CNVs. To demonstrate the potential impact of confounders, we genotyped rare CNV events in 2,415  unaffected  controls with Affymetrix 6.0; we then applied standard pathway analyses using four sets of brain-function genes and observed an apparently highly significant enrichment for each set. The enrichment is simply driven by the large size of brain-function genes. Instead, we propose a case-control statistical test,  cnv-enrichment-test , to compare the rate of CNVs impacting specific gene sets in cases versus controls. With simulations, we demonstrate that  cnv-enrichment-test  is robust to case-control differences in CNV size, CNV rate, and systematic differences in gene size. Finally, we apply  cnv-enrichment-test  to rare CNV events published by the International Schizophrenia Consortium (ISC). This approach reveals nominal evidence of case-association in  neuronal-activity  and the  learning  gene sets, but not the other two examined gene sets. The  neuronal-activity  genes have been associated in a separate set of schizophrenia cases and controls; however, testing in independent samples is necessary to definitively confirm this association. Our method is implemented in the PLINK software package.

Accurately Assessing the Risk of Schizophrenia Conferred by Rare Copy-Number Variation Affecting Genes with Brain Function