Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

• Published in: Nature genetics Vol. 49; no. 1; pp. 27 - 35
• Main Authors: Merico, Daniele, Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M, Malhotra, Dheeraj, Alexander, Madeline, Belliveau, Richard A, Bergen, Sarah E, Bertalan, Marcelo, Bevilacqua, Elizabeth, Cantor, Rita M, Carrera, Noa, Cormican, Paul, Crespo-Facorro, Benedicto, Curtis, David, Davidson, Michael, Degenhardt, Franziska, Del Favero, Jurgen, DeLisi, Lynn E, Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Essioux, Laurent, Farrell, Martilias S, Freedman, Robert, Freimer, Nelson B, Georgieva, Lyudmila, Gershon, Elliot S, Giegling, Ina, Godard, Stephanie, Goldstein, Jacqueline I, Hamshere, Marian L, Hartmann, Annette M, Hofman, Andrea, Kähler, Anna K, Kalaydjieva, Luba, Kelly, Brian J, Lee, S Hong, Legge, Sophie E, Lerer, Bernard, Levy, Deborah L, Maher, Brion S, Mattingsdal, Morten, McDonald, Colm, Metspalu, Andres, Milanova, Vihra, Morris, Derek W, Murray, Robin M, Nestadt, Gerald, Nicodemus, Kristin K, Nordin, Annelie, Oh, Sang-Yun, Olsen, Line, Van Os, Jim, Pantelis, Christos, Pers, Tune H, Powell, John, Price, Alkes, Pulver, Ann E, Purcell, Shaun M, Rasmussen, Henrik B, Richards, Alexander L, Roussos, Panos, Schall, Ulrich, Schwab, Sibylle G, Smoller, Jordan W, Spencer, Chris C A, Stahl, Eli A, Stroup, T Scott, Suvisaari, Jaana, Svrakic, Dragan M, Szatkiewicz, Jin P, Veijola, Juha, Waddington, John, Webb, Bradley T, Williams, Nigel M, Williams, Stephanie, Wolen, Aaron R, Adolfsson, Rolf, Blackwood, Douglas H R, Bramon, Elvira, Buxbaum, Joseph D, Collier, David A, Daly, Mark J, Darvasi, Ariel, Domenici, Enrico, Gill, Michael, Iwata, Nakao, Jablensky, Assen V, Jönsson, Erik G, Kirov, George, Knight, Jo, Levinson, Douglas F, Ophoff, Roel A, Owen, Michael J, Rietschel, Marcella, Rujescu, Dan, O'Donovan, Michael C, Neale, Benjamin M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2017; Nature Publishing Group
• Subjects: 45; 45/23; 631/208/212; 692/308/2056; 692/699/476/1799; Agriculture; Analysis; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Case-Control Studies; Consortia; Copy number variations; Data processing; Datasets; Development and progression; DNA Copy Number Variations; DNA Copy Number Variations - genetics; Female; Gene Function; Genetic aspects; Genetic Loci; Genetic Loci - genetics; Genetic Markers; Genetic Markers - genetics; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotype; Human Genetics; Human health and pathology; Humans; Life Sciences; Male; Mental disorders; Meta-analysis; Pipelines; Quality control; Risk Factors; Schizophrenia; Schizophrenia - genetics; Studies; Working groups
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3725

The CNV analysis group of the Psychiatric Genomic Consortium analyzes a large schizophrenia cohort to examine genomic copy number variants (CNVs) and disease risk. They find an enrichment of CNV burden in cases versus controls and identify 8 genome-wide significant loci as well as novel suggestive loci conferring either risk or protection to schizophrenia. Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10 −15 ), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10 −6 ). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10 −11 ) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10 −5 ). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 ( NRXN1 ), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.