title: Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia.
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.
authors.affiliation: 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.
authors.forename: Jennifer Gladys
authors.initials: JG
authors.lastname: Mulle
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Pulver
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine.
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine.
authors.forename: Paula S
authors.initials: PS
authors.lastname: Wolyniec
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University.
authors.forename: Anne F
authors.initials: AF
authors.lastname: Dodd
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cutler
authors.affiliation: 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.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sebat
authors.affiliation: Beyster Center for Genomics of Psychiatric Diseases; Department of PsychiatryUniversity of California, San Diego, La Jolla, California.
authors.forename: Dheeraj
authors.initials: D
authors.lastname: Malhotra
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine.
authors.forename: Gerald
authors.initials: G
authors.lastname: Nestadt
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Conrad
authors.affiliation: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hurles
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, United Kingdom.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Barnes
authors.affiliation: Fujita Health University School of Medicine, Toyake, Aichi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Fujita Health University School of Medicine, Toyake, Aichi, Japan.
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Levinson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston; Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, Illinois.
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Gejman
authors.affiliation: Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston; Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, Illinois.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Sanders
authors.affiliation: Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston; Department of Psychiatry and Behavioral Sciences, University of Chicago, Chicago, Illinois.
authors.forename: Jubao
authors.initials: J
authors.lastname: Duan
authors.affiliation: Department of Forensic Biology, Office of Chief Medical Examiner of the City of New York.
authors.forename: Adele A
authors.initials: AA
authors.lastname: Mitchell
authors.affiliation: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York.
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.affiliation: 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.
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
authors.affiliation: 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.
authors.forename: Colm T
authors.initials: CT
authors.lastname: O'Dushlaine
authors.affiliation: Department of Psychological Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Detelina
authors.initials: D
authors.lastname: Grozeva
authors.affiliation: Department of Psychological Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.affiliation: Department of Psychological Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Hultman
authors.affiliation: 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.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kähler
authors.affiliation: Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Sullivan
authors.affiliation: Department of Psychological Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Kirov
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia; Departments of Biochemistry and Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Warren
mesh_terms: D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D012559:Schizophrenia / Q000150:complications / Q000235:genetics*; D018980:Williams Syndrome / Q000150:complications / Q000235:genetics*
keywords: 7q11.23 duplication syndrome; Autism; Williams-Beuren syndrome; psychiatric genetics; schizophrenia; schizophrenia genetics