Reciprocal Duplication of the Williams-Beuren Syndrome Deletion on Chromosome 7q11.23 Is Associated with Schizophrenia

• Type of Material: Article
• Authors: Jennifer Mulle, Emory University; Ann E. Pulver, Emory University; John M. McGrath, Emory University; Paula Wolyniec, Emory University; Anne F. Dodd, Emory University; David Cutler, Emory University; Jonathan Sebat, University of California San Diego; Dheeraj Malhotra, University of California San Diego; Gerald Nestadt, Emory University; Donald F. Conrad, Wellcome Trust Sanger Institute; Matthew Hurles, Wellcome Trust Sanger Institute; Chris P. Barnes, University College London; Masashi Ikeda, Fujita Health University; Nakao Iwata, Fujita Health University; Douglas F. Levinson, Stanford University; Pablo V. Gejman, NorthShore University Health System; Alan R. Sanders, NorthShore University Health System; Jubao Duan, NorthShore University Health System; Adele A. Mitchell, Office of Chief Medical Examiner of the City of New York; Inga Peter, Mount Sinai School of Medicine; Pamela Sklar, Massachusetts General Hospital; Colm T. O'Dushlaine, Broad Institute of MIT and Harvard; Detelina Grozeva, Cardiff University; Michael C. O'Donovan, Cardiff University; Michael J. Owen, Cardiff University; Christina M. Hultman, Karolinska Institutet; Anna K. Kahler, Karolinska Institutet; Patrick F. Sullivan, University of North Carolina; George Kirov, Cardiff University; Stephen Warren, Emory University
• Language: English
• Date: 2014-03-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Society of Biological Psychiatry.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2013.05.040
• Title of Journal or Parent Work: Biological Psychiatry
• ISSN: 0006-3223
• Volume: 75
• Issue: 5
• Start Page: 371
• End Page: 377
• Grant/Funding Information: Funding for this study was provided by NIH grants MH080129 and MH083722 to STW, and a NARSAD Young Investigator Award to JGM.; Samples and associated phenotype data for the MGS GWAS study were collected under the following grants: NIMH Schizophrenia Genetics Initiative U01s: MH46276 (CR Cloninger), MH46289 (C Kaufmann), and MH46318 (MT Tsuang); and MGS Part 1 (MGS1) and Part 2 (MGS2) R01s: MH67257 (NG Buccola), MH59588 (BJ Mowry), MH59571 (PV Gejman), MH59565 (Robert Freedman), MH59587 (F Amin), MH60870 (WF Byerley), MH59566 (DW Black), MH59586 (JM Silverman), MH61675 (DF Levinson), and MH60879 (CR Cloninger).; Support was provided by MH077139 (PFS), the Stanley Center for Psychiatric Research at the Broad Institute from a grant from Stanley Medical Research Institute, the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, ALF grant from Swedish County Council, and Söderström Königska Foundation. Funding support for the companion studies, Genome-Wide Association Study of Schizophrenia (GAIN) and Molecular Genetics of Schizophrenia - nonGAIN Sample (MGS_nonGAIN), was provided by Genomics Research Branch at NIMH and the genotyping and analysis of samples was provided through the Genetic Association Information Network (GAIN) and under the MGS U01s: MH79469 and MH79470.
• Keywords: Neurosciences & Neurology; Life Sciences & Biomedicine; EPILEPSY; HIGH-RISK; Psychiatry; CANDIDATE GENES; schizophrenia genetics; REARRANGEMENTS; schizophrenia; POPULATION; AUTISM; Neurosciences; CARDIO-FACIAL SYNDROME; 7q11.23 duplication syndrome; Autism; Science & Technology; Williams-Beuren syndrome; psychiatric genetics; SUPRAVALVULAR AORTIC STENOSIS; MICRODELETIONS; COPY-NUMBER VARIANTS
• Research Categories: Biology, Neuroscience; Psychology, Cognitive

Abstract

Background Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome. Methods We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ. Results We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95% confidence interval: 3.13-922.6, p value 5.5 × 10 -5; adjusted odds ratio 10.8, 95% confidence interval: 1.46-79.62, p value.007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication. Conclusions We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ.