TY - JOUR
T1 - Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function
AU - The International schizophrenia consortium
AU - Raychaudhuri, Soumya
AU - Korn, Joshua M.
AU - McCarroll, Steven A.
AU - Altshuler, David
AU - Sklar, Pamela
AU - Purcell, Shaun
AU - Daly, Mark J.
AU - Purcell, Shaun
AU - Stone, Jennifer
AU - Bergen, Sarah
AU - O'Dushlaine, Colm
AU - Ruderfer, Douglas
AU - Sklar, Pamela
AU - Scolnick, Edward
AU - Chambert, Kimberly
AU - O'Donovan, Michael
AU - Kirov, George
AU - Craddock, Nick
AU - Holmans, Peter
AU - Williams, Nigel
AU - Georgieva, Lucy
AU - Nikolov, Ivan
AU - Norton, Nadine
AU - Williams, H.
AU - Toncheva, Draga
AU - Milanova, Vihra
AU - Owen, Michael
AU - Hultman, Christina
AU - Lichtenstein, Paul
AU - Thelander, Emma
AU - Sullivan, Patrick
AU - Morris, Derek
AU - Kenny, Elaine
AU - Waddington, John
AU - Gill, Michael
AU - Corvin, Aiden
AU - McQuillin, Andrew
AU - Choudhury, Khalid
AU - Datta, Susmita
AU - Pimm, Jonathan
AU - Thirumalai, Srinivasa
AU - Puri, Vinay
AU - Krasucki, Robert
AU - Lawrence, Jacob
AU - Quested, Digby
AU - Bass, Nicholas
AU - Curtis, David
AU - Gurling, Hugh
AU - Crombie, Caroline
AU - Fraser, Gillian
PY - 2010/9/1
Y1 - 2010/9/1
N2 - 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.
AB - 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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U2 - 10.1371/journal.pgen.1001097
DO - 10.1371/journal.pgen.1001097
M3 - Article
C2 - 20838587
AN - SCOPUS:78049450213
SN - 1553-7390
VL - 6
JO - PLoS genetics
JF - PLoS genetics
IS - 9
M1 - e1001097
ER -