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Original Article
March 2013

Implication of a Rare Deletion at Distal 16p11.2 in Schizophrenia

Author Affiliations

Author Affiliations: Division of Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, New York (Drs Guha, Kane, A. K. Malhotra, and Lencz); Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, Wales (Mr Rees and Drs Ivanov, Owen, O’Donovan, and Kirov); Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel (Dr Darvasi); Fujita Health University School of Medicine, Toyoake, Japan (Drs Ikeda and Iwata); Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School (Drs Bergen and Purcell), and Center for Human Genetics Research, Massachusetts General Hospital (Drs Bergen and Purcell), Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Massachusetts (Drs Bergen, Moran, and Purcell and Ms Chambert); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Drs Magnusson and Hultman); Department of Psychiatry, Trinity College Dublin (Drs Cormican, Morris, Gill, and Corvin), and Health Research Board (Dr Walsh), Dublin, Ireland; Institute of Human Genetics (Drs Cichon, Nöthen, and Degenhardt and Mr Priebe) and Department of Genomics, Life and Brain Center (Drs Cichon and Degenhardt and Mr Priebe), University of Bonn, and German Center for Neurodegenerative Diseases (Dr Nöthen), Bonn, Germany; Institute of Neuroscience and Medicine, Research Center Juelich, Juelich, Germany (Dr Cichon); IST/High Performance and Research Computing, University of Medicine and Dentistry of New Jersey, Newark (Dr Rosenfeld); Robert S. Boas Center for Human Genetics and Genomics (Drs Lee and Gregersen) and Center for Psychiatric Neuroscience (Drs Kane, A. K. Malhotra, and Lencz), The Feinstein Institute for Medical Research, Manhasset, New York; Department of Psychiatry, Hofstra University School of Medicine, Long Island, New York (Drs Kane, A. K. Malhotra, and Lencz); Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany (Dr Rietschel, Mr Breuer, and Ms Strohmaier); Division of Psychiatric Genomics, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York (Mr Ruderfer and Drs Purcell and Sklar); Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem Research Institute, Evanston, Illinois (Drs Sanders and Gejman); Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, Illinois (Drs Sanders and Gejman); National Cancer Institute, Bethesda, Maryland (Dr Shi); Virginia Institute for Psychiatry and Behavioral Genetics (Dr Kendler) and Department of Psychiatry (Dr Riley), School of Medicine, Virginia Commonwealth University, Richmond; Department of Psychiatry, Queens University, Belfast, Ireland (Dr O’Neill); Beyster Center for Genomics of Psychiatric Diseases, University of California, San Diego, La Jolla (Drs D. Malhotra and Sebat); Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill (Dr Sullivan); Stanley Institute for Cognitive Genomics, Woodbury Genome Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, Cold Spring, New York (Mr McCarthy); and Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California (Dr Levinson).

Group Information: Pablo V. Gejman, MD, takes authorship responsibility for the Molecular Genetics of Schizophrenia Consortium, and Aiden Corvin, MRCPsych, PhD, takes authorship responsibility for the Wellcome Trust Case Control Consortium 2.

JAMA Psychiatry. 2013;70(3):253-260. doi:10.1001/2013.jamapsychiatry.71

Context Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication.

Objective To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples.

Design Genetic association study of microarray data.

Setting Samples of DNA were collected at 9 sites from different countries.

Participants Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parent-offspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12 398 cases and 17 945 controls.

Main Outcome Measures Statistically increased rate of specific copy number variations in cases vs controls.

Results One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13 850 cases (0.094%) and 3 of 19 954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P = .001, Fisher exact test).

Conclusions Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia.