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Implication of a rare deletion at distal 16p11.2 in schizophrenia

Guha, Saurav, Rees, Elliott, Darvasi, Ariel, Ivanov, Dobril, Ikeda, Masashi, Bergen, Sarah E., Magnusson, Patrik K., Cormican, Paul, Morris, Derek, Gill, Michael, Cichon, Sven, Rosenfeld, Jeffrey A., Lee, Annette, Gregersen, Peter K., Kane, John M., Malhotra, Anil K., Rietschel, Marcella, Nöthen, Markus M., Degenhardt, Franziska, Priebe, Lutz, Breuer, René, Strohmaier, Jana, Ruderfer, Douglas M., Moran, Jennifer L., Chambert, Kimberly D., Sanders, Alan R., Shi, Jianxin, Kendler, Kenneth, Riley, Brien, O’Neill,, Tony, Walsh, Dermot, Malhotra, Dheeraj, Corvin, Aiden, Purcell, Shaun, Sklar, Pamela, Iwata, Nakao, Hultman, Christina M., Sullivan, Patrick F., Sebat, Jonathan, McCarthy, Shane, Gejman, Pablo V., Levinson, Douglas F., Owen, Michael John, O'Donovan, Michael Conlon, Lencz, Todd and Kirov, George 2013. Implication of a rare deletion at distal 16p11.2 in schizophrenia. JAMA Psychiatry 70 (3) , pp. 253-260. 10.1001/2013.jamapsychiatry.71

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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. Uncovering the genetic factors underlying schizophrenia (SZ) has proven difficult despite heritability estimates of up to 80%.1 Copy number variations (CNVs) at several loci show consistently replicated evidence for association with SZ.2- 3 These CNVs are individually very rare, are not fully penetrant, and are found cumulatively in approximately 2% of SZ cases; therefore, large samples were required to establish their association. Given their low baseline frequency, further CNV susceptibility loci likely have yet to be discovered. In the present study, we report the identification of a CNV locus at distal 16p11.2 that increases the risk for SZ. Findings pointing to a possible association between this locus and SZ were obtained independently by 2 teams of investigators. During the process of obtaining replication data, the 2 groups became aware of each other's work and decided to combine results from their discovery and replication cohorts. Using high-resolution microarrays, one group (from New York and Israel) examined an SZ case-control cohort from the Ashkenazi Jewish (AJ) population, whereas the other group (from Cardiff, Wales) examined a cohort of parent-offspring trios from Bulgaria (BG). Because of the need for large-scale replication, we contacted research groups worldwide who were willing to share raw data from microarray-based CNV studies in cohorts of SZ cases and controls and obtained data from a total of approximately 34 000 individuals.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Additional Information: Produced for the Molecular Genetics of Schizophrenia Consortium and the Wellcome Trust Case Control Consortium 2
Publisher: American Medical Association
ISSN: 2168-622X
Date of Acceptance: 19 July 2012
Last Modified: 13 Nov 2018 21:49

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