title: Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation.
abstract: BACKGROUND
  Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD.
  
  
  METHODS
  We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD.
  
  
  RESULTS
  We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominalp= 1.85 × 10-03; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1andPTPRD), and postsynaptic scaffolding (DLGAP1andDLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identifiedBTBD9as a candidate gene for OCD. We also sequenced exomes of ten "CNV positive" trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion inDRD4.
  
  
  CONCLUSIONS
  Our findings suggest that rare CNVs may contribute to the etiology of OCD.
authors: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Matthew J
authors: MJ
authors: Gazzellone
authors: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Mehdi
authors: M
authors: Zarrei
authors: Department of Psychiatry and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Christie L
authors: CL
authors: Burton
authors: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Susan
authors: S
authors: Walker
authors: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Mohammed
authors: M
authors: Uddin
authors: Department of Psychiatry and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.|Mathison Centre for Mental Health Research and Education and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB Canada.
authors: S M
authors: SM
authors: Shaheen
authors: Department of Psychiatry and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Julie
authors: J
authors: Coste
authors: Department of Psychiatry and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.|Faculty of Medicine, University of Toronto, Toronto, ON Canada.
authors: Rageen
authors: R
authors: Rajendram
authors: Department of Psychiatry and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Reva J
authors: RJ
authors: Schachter
authors: Department of Psychiatry and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Marlena
authors: M
authors: Colasanto
authors: Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI USA.
authors: Gregory L
authors: GL
authors: Hanna
authors: Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI USA.|The Children's Hospital of Michigan, Detroit, MI USA.
authors: David R
authors: DR
authors: Rosenberg
authors: Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMaster University, St. Joseph's Healthcare, Hamilton, ON Canada.
authors: Noam
authors: N
authors: Soreni
authors: Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI USA.
authors: Kate D
authors: KD
authors: Fitzgerald
authors: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Christian R
authors: CR
authors: Marshall
authors: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Janet A
authors: JA
authors: Buchanan
authors: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
authors: Daniele
authors: D
authors: Merico
authors: Department of Psychiatry and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.|Mathison Centre for Mental Health Research and Education and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB Canada.|Departments of Psychiatry and Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB Canada.
authors: Paul D
authors: PD
authors: Arnold
authors: The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.|Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, ON Canada.
authors: Stephen W
authors: SW
authors: Scherer
keywords: Copy number variation; Obsessive-compulsive disorder; Pediatrics; Whole-exome sequencing