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Biol Psychiatry. 2014 Mar 1;75(5):371-7. doi: 10.1016/j.biopsych.2013.05.040. Epub 2013 Jul 17.

Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia.

Author information

1
Department of Epidemiology, Rollins School of Public Health, Emory University; Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia. Electronic address: jmulle@emory.edu.
2
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
3
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine.
4
Department of Epidemiology, Rollins School of Public Health, Emory University.
5
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
6
Beyster Center for Genomics of Psychiatric Diseases; Department of PsychiatryUniversity of California, San Diego, La Jolla, California; Department of Cellular Molecular and Molecular Medicine, University of California, San Diego, La Jolla, California; Institute for Genomic Medicine, University of California, San Diego, La Jolla, California.
7
Beyster Center for Genomics of Psychiatric Diseases; Department of PsychiatryUniversity of California, San Diego, La Jolla, California.
8
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge.
9
Department of Cell and Developmental Biology, University College London, London, United Kingdom.
10
Fujita Health University School of Medicine, Toyake, Aichi, Japan.
11
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
12
Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston; Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, Illinois.
13
Department of Forensic Biology, Office of Chief Medical Examiner of the City of New York.
14
Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York.
15
Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts; Division of Psychiatric Genomics, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York.
16
Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston; Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
17
Department of Psychological Medicine, Cardiff University, Cardiff, United Kingdom.
18
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
19
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
20
Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina.
21
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia; Departments of Biochemistry and Pediatrics, Emory University School of Medicine, Atlanta, Georgia.

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.

KEYWORDS:

7q11.23 duplication syndrome; Autism; Williams-Beuren syndrome; psychiatric genetics; schizophrenia; schizophrenia genetics

PMID:
23871472
PMCID:
PMC3838485
DOI:
10.1016/j.biopsych.2013.05.040
[Indexed for MEDLINE]
Free PMC Article

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