Journal Article


Mark J Daly
Shaun Purcell
Pamela Sklar
Aiden Peter Corvin
David Altshuler
Derek Morris
Steven A A McCarroll
Elaine Kenny
Joshua M Korn
Michael Gill
and 1 others



case control studies genetic predisposition to disease risk assessment genetic copy number variation human software package genome human case control computer simulation genome brain life sciences models genetic databases gene deletion humans brain function schizophrenia dna copy number variations neuroscience genes databases genetic neuronal activity

Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. (2010)

Abstract 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 brainfunctions. 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, cnvenrichment- 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.
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Full list of authors on original publication

Mark J Daly, Shaun Purcell, Pamela Sklar, Aiden Peter Corvin, David Altshuler, Derek Morris, Steven A A McCarroll, Elaine Kenny, Joshua M Korn, Michael Gill and 1 others

Experts in our system

Aiden Corvin
Trinity College Dublin
Total Publications: 218
Derek Morris
Trinity College Dublin
Total Publications: 168
Elaine Kenny
Trinity College Dublin
Total Publications: 32
Michael Gill
Trinity College Dublin
Total Publications: 294