title: Copy number variation in obsessive-compulsive disorder and tourette syndrome: a cross-disorder study.
abstract: OBJECTIVE
  Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date.
  
  
  METHODS
  The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios.
  
  
  RESULTS
  Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%).
  
  
  CONCLUSIONS
  Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.
authors: Massachusetts General Hospital, Boston; American University, Washington, DC; Harvard-MIT Broad Institute, Boston.
authors: Lauren M
authors: LM
authors: McGrath
authors: Massachusetts General Hospital, Boston; Harvard-MIT Broad Institute, Boston.
authors: Dongmei
authors: D
authors: Yu
authors: University of Toronto and the Hospital for Sick Children, Toronto.
authors: Christian
authors: C
authors: Marshall
authors: University of Chicago.
authors: Lea K
authors: LK
authors: Davis
authors: University of Toronto and the Hospital for Sick Children, Toronto.
authors: Bhooma
authors: B
authors: Thiruvahindrapuram
authors: University of Toronto and the Hospital for Sick Children, Toronto.
authors: Bingbin
authors: B
authors: Li
authors: University of São Paulo Medical School.
authors: Carolina
authors: C
authors: Cappi
authors: Massachusetts General Hospital, Boston.
authors: Gloria
authors: G
authors: Gerber
authors: Massachusetts General Hospital, Boston.
authors: Aaron
authors: A
authors: Wolf
authors: Massachusetts General Hospital, Boston.
authors: Frederick A
authors: FA
authors: Schroeder
authors: Massachusetts General Hospital, Boston.
authors: Lisa
authors: L
authors: Osiecki
authors: Harvard-MIT Broad Institute, Boston.
authors: Colm
authors: C
authors: O'Dushlaine
authors: Massachusetts General Hospital, Boston.
authors: Andrew
authors: A
authors: Kirby
authors: Massachusetts General Hospital, Boston.
authors: Cornelia
authors: C
authors: Illmann
authors: Massachusetts General Hospital, Boston.
authors: Stephen
authors: S
authors: Haddad
authors: Massachusetts General Hospital, Boston.
authors: Patience
authors: P
authors: Gallagher
authors: Massachusetts General Hospital, Boston.
authors: Jesen A
authors: JA
authors: Fagerness
authors: University of Toronto and the Hospital for Sick Children, Toronto; Toronto Western Research Institute, University Health Network, Toronto.
authors: Cathy L
authors: CL
authors: Barr
authors: Università Vita-Salute San Raffaele, Milan.
authors: Laura
authors: L
authors: Bellodi
authors: Hadassah-Hebrew University Medical Center, Jerusalem.
authors: Fortu
authors: F
authors: Benarroch
authors: Johns Hopkins University School of Medicine, Baltimore.
authors: O Joseph
authors: OJ
authors: Bienvenu
authors: University of Iowa College of Medicine, Iowa City.
authors: Donald W
authors: DW
authors: Black
authors: Yale University School of Medicine, New Haven, CT.
authors: Michael H
authors: MH
authors: Bloch
authors: North Shore-Long Island Jewish Medical Center, New Hyde Park, NY; New York University Medical Center, New York.
authors: Ruth D
authors: RD
authors: Bruun
authors: North Shore-Long Island Jewish Medical Center, New Hyde Park, NY; Hofstra University School of Medicine, Hempstead, NY.
authors: Cathy L
authors: CL
authors: Budman
authors: Instituto Nacional de Psiquiatría Ramon de la Fuente Muñiz, Mexico.
authors: Beatriz
authors: B
authors: Camarena
authors: Utrecht University and VU Medical Center, Amsterdam.
authors: Danielle C
authors: DC
authors: Cath
authors: Ospedale San Raffaele, Milan.
authors: Maria C
authors: MC
authors: Cavallini
authors: University of Montreal.
authors: Sylvain
authors: S
authors: Chouinard
authors: Yale University School of Medicine, New Haven, CT.
authors: Vladimir
authors: V
authors: Coric
authors: Johns Hopkins University School of Medicine, Baltimore.
authors: Bernadette
authors: B
authors: Cullen
authors: Robert Debre University Hospital, Paris and the French National Science Foundation, Creteil, France; Institut Pasteur, Paris.
authors: Richard
authors: R
authors: Delorme
authors: Netherlands Institute for Neuroscience, Amsterdam; Academic Medical Center, Amsterdam.
authors: Damiaan
authors: D
authors: Denys
authors: Academic Medical Center, Amsterdam.
authors: Eske M
authors: EM
authors: Derks
authors: University of Montreal.
authors: Yves
authors: Y
authors: Dion
authors: Federal University of São Paulo.
authors: Maria C
authors: MC
authors: Rosário
authors: University of New South Wales, Australia.
authors: Valsama
authors: V
authors: Eapen
authors: University of Chicago.
authors: Patrick
authors: P
authors: Evans
authors: University of Munich.
authors: Peter
authors: P
authors: Falkai
authors: Yale University School of Medicine, New Haven, CT.
authors: Thomas V
authors: TV
authors: Fernandez
authors: Hospital Nacional de Niños, San Jose, Costa Rica; Clinica Herrera Amighetti, Avenida Escazú, San José, Costa Rica.
authors: Helena
authors: H
authors: Garrido
authors: Massachusetts General Hospital, Boston.
authors: Daniel
authors: D
authors: Geller
authors: University Medicine Greifswald, Greifswald, Germany.
authors: Hans J
authors: HJ
authors: Grabe
authors: Johns Hopkins University School of Medicine, Baltimore.
authors: Marco A
authors: MA
authors: Grados
authors: Brown Medical School, Providence, RI.
authors: Benjamin D
authors: BD
authors: Greenberg
authors: Shaare Zedek Medical Center, Jerusalem.
authors: Varda
authors: V
authors: Gross-Tsur
authors: University of Zurich.
authors: Edna
authors: E
authors: Grünblatt
authors: Rutgers University, Piscataway Township, NJ.
authors: Gary A
authors: GA
authors: Heiman
authors: University of Stellenbosch, South Africa.
authors: Sian M J
authors: SM
authors: Hemmings
authors: Hospital Nacional de Niños, San Jose, Costa Rica.
authors: Luis D
authors: LD
authors: Herrera
authors: Federal University of São Paulo.
authors: Ana G
authors: AG
authors: Hounie
authors: Baylor College of Medicine, Houston.
authors: Joseph
authors: J
authors: Jankovic
authors: Centre for Addiction and Mental Health, Toronto.
authors: James L
authors: JL
authors: Kennedy
authors: Yale University School of Medicine, New Haven, CT.
authors: Robert A
authors: RA
authors: King
authors: Atlantic Neuroscience Institute, Summit, NJ.
authors: Roger
authors: R
authors: Kurlan
authors: Carracci Medical Group, Mexico City.
authors: Nuria
authors: N
authors: Lanzagorta
authors: Robert Debre University Hospital, Paris and the French National Science Foundation, Creteil, France; Institut Mondor de Recherche Biomédicale, Créteil, France.
authors: Marion
authors: M
authors: Leboyer
authors: Yale University School of Medicine, New Haven, CT.
authors: James F
authors: JF
authors: Leckman
authors: University of Bonn, Germany.
authors: Leonhard
authors: L
authors: Lennertz
authors: University of Stellenbosch, South Africa.
authors: Christine
authors: C
authors: Lochner
authors: University of California at San Francisco School of Medicine.
authors: Thomas L
authors: TL
authors: Lowe
authors: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
authors: Gholson J
authors: GJ
authors: Lyon
authors: University of California, Irvine.
authors: Fabio
authors: F
authors: Macciardi
authors: University of Bonn, Germany.
authors: Wolfgang
authors: W
authors: Maier
authors: University of California, Los Angeles (UCLA) School of Medicine.
authors: James T
authors: JT
authors: McCracken
authors: University of Utah, Salt Lake City.
authors: William
authors: W
authors: McMahon
authors: National Institute of Mental Health (NIMH) Intramural Research Program, Bethesda, MD.
authors: Dennis L
authors: DL
authors: Murphy
authors: Medical City Dallas Hospital.
authors: Allan L
authors: AL
authors: Naarden
authors: Massachusetts General Hospital, Boston; Harvard-MIT Broad Institute, Boston.
authors: Benjamin M
authors: BM
authors: Neale
authors: University of California, Los Angeles (UCLA) School of Medicine.
authors: Erika
authors: E
authors: Nurmi
authors: Yale University School of Medicine, New Haven, CT.
authors: Andrew J
authors: AJ
authors: Pakstis
authors: Zilkha Neurogenetic Institute, Los Angeles.
authors: Michele T
authors: MT
authors: Pato
authors: Zilkha Neurogenetic Institute, Los Angeles.
authors: Carlos N
authors: CN
authors: Pato
authors: University of California, Los Angeles (UCLA) School of Medicine.
authors: John
authors: J
authors: Piacentini
authors: Yale University School of Medicine, New Haven, CT.
authors: Christopher
authors: C
authors: Pittenger
authors: Shaare Zedek Medical Center, Jerusalem.
authors: Yehuda
authors: Y
authors: Pollak
authors: University of California at San Francisco School of Medicine.
authors: Victor I
authors: VI
authors: Reus
authors: University of Toronto and the Hospital for Sick Children, Toronto; Sunnybrook Health Sciences Centre, Toronto.
authors: Margaret A
authors: MA
authors: Richter
authors: Johns Hopkins University School of Medicine, Baltimore.
authors: Mark
authors: M
authors: Riddle
authors: University College London.
authors: Mary M
authors: MM
authors: Robertson
authors: Wayne State University and Detroit Medical Center, Detroit.
authors: David
authors: D
authors: Rosenberg
authors: Montreal Neurological Institute.
authors: Guy A
authors: GA
authors: Rouleau
authors: University of Cologne, Germany.
authors: Stephan
authors: S
authors: Ruhrmann
authors: Federal University of São Paulo; Universidade Federal da Bahia, Salvador, Bahia, Brazil.
authors: Aline S
authors: AS
authors: Sampaio
authors: Johns Hopkins University School of Medicine, Baltimore.
authors: Jack
authors: J
authors: Samuels
authors: University of Toronto and the Hospital for Sick Children, Toronto; Toronto Western Research Institute, University Health Network, Toronto.
authors: Paul
authors: P
authors: Sandor
authors: University of California at San Francisco School of Medicine.
authors: Brooke
authors: B
authors: Sheppard
authors: Johns Hopkins University School of Medicine, Baltimore.
authors: Harvey S
authors: HS
authors: Singer
authors: VU Amsterdam and Erasmus University Medical Centre, Rotterdam; VU University Amsterdam; VU Medical Center, Amsterdam.
authors: Jan H
authors: JH
authors: Smit
authors: University of Cape Town, South Africa.
authors: Dan J
authors: DJ
authors: Stein
authors: Rutgers University, Piscataway Township, NJ.
authors: Jay A
authors: JA
authors: Tischfield
authors: University of São Paulo Medical School.
authors: Homero
authors: H
authors: Vallada
authors: Vanderbilt University, Nashville, TN.
authors: Jeremy
authors: J
authors: Veenstra-VanderWeele
authors: University of Zurich; University of Würzburg.
authors: Susanne
authors: S
authors: Walitza
authors: Johns Hopkins University School of Medicine, Baltimore.
authors: Ying
authors: Y
authors: Wang
authors: National Institute of Mental Health (NIMH) Intramural Research Program, Bethesda, MD.
authors: Jens R
authors: JR
authors: Wendland
authors: National Institute of Mental Health (NIMH) Intramural Research Program, Bethesda, MD.
authors: Yin Yao
authors: YY
authors: Shugart
authors: University of São Paulo Medical School.
authors: Euripedes C
authors: EC
authors: Miguel
authors: Carracci Medical Group, Mexico City.
authors: Humberto
authors: H
authors: Nicolini
authors: Erasmus Medical Center Rotterdam, the Netherlands.
authors: Ben A
authors: BA
authors: Oostra
authors: University of Bonn, Germany.
authors: Rainald
authors: R
authors: Moessner
authors: University of Bonn, Germany.
authors: Michael
authors: M
authors: Wagner
authors: University College London.
authors: Andres
authors: A
authors: Ruiz-Linares
authors: German Center for Neurodegenerative Diseases, Bonn and VU Medical Center Amsterdam.
authors: Peter
authors: P
authors: Heutink
authors: Johns Hopkins University School of Medicine, Baltimore.
authors: Gerald
authors: G
authors: Nestadt
authors: University of California, Los Angeles (UCLA) School of Medicine; Semel Institute for Neuroscience and Human Behavior, UCLA.
authors: Nelson
authors: N
authors: Freimer
authors: Massachusetts General Hospital, Boston; Harvard-MIT Broad Institute, Boston.
authors: Tracey
authors: T
authors: Petryshen
authors: VU Amsterdam and Erasmus University Medical Centre, Rotterdam.
authors: Danielle
authors: D
authors: Posthuma
authors: Massachusetts General Hospital, Boston.
authors: Michael A
authors: MA
authors: Jenike
authors: University of Chicago.
authors: Nancy J
authors: NJ
authors: Cox
authors: University of Michigan, Ann Arbor, MI.
authors: Gregory L
authors: GL
authors: Hanna
authors: University of São Paulo Medical School.
authors: Helena
authors: H
authors: Brentani
authors: University of Toronto and the Hospital for Sick Children, Toronto.
authors: Stephen W
authors: SW
authors: Scherer
authors: University of Toronto and the Hospital for Sick Children, Toronto.
authors: Paul D
authors: PD
authors: Arnold
authors: Massachusetts General Hospital, Boston; University of British Columbia, Vancouver.
authors: S Evelyn
authors: SE
authors: Stewart
authors: University of California at San Francisco School of Medicine.
authors: Carol A
authors: CA
authors: Mathews
authors: Zilkha Neurogenetic Institute, Los Angeles.
authors: James A
authors: JA
authors: Knowles
authors: University of Illinois at Chicago.
authors: Edwin H
authors: EH
authors: Cook
authors: Massachusetts General Hospital, Boston.
authors: David L
authors: DL
authors: Pauls
authors: Zilkha Neurogenetic Institute, Los Angeles.
authors: Kai
authors: K
authors: Wang
authors: Massachusetts General Hospital, Boston; Brigham and Womens Hospital, Boston; Harvard-MIT Broad Institute, Boston. Electronic address: jscharf@partners.org.
authors: Jeremiah M
authors: JM
authors: Scharf
mesh_terms: D000293:Adolescent; D056915:DNA Copy Number Variations; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009771:Obsessive-Compulsive Disorder / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D005879:Tourette Syndrome / Q000175:diagnosis / Q000235:genetics*
keywords: 16p13.11; Tourette syndrome; copy number variation; genetics; obsessive-compulsive disorder