title: Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.
abstract: Studies of rare genetic variation have identified molecular pathways conferring risk for developmental neuropsychiatric disorders. To date, no published whole-exome sequencing studies have been reported in obsessive-compulsive disorder (OCD). We sequenced all the genome coding regions in 20 sporadic OCD cases and their unaffected parents to identify rare de novo (DN) single-nucleotide variants (SNVs). The primary aim of this pilot study was to determine whether DN variation contributes to OCD risk. To this aim, we evaluated whether there is an elevated rate of DN mutations in OCD, which would justify this approach toward gene discovery in larger studies of the disorder. Furthermore, to explore functional molecular correlations among genes with nonsynonymous DN SNVs in OCD probands, a protein-protein interaction (PPI) network was generated based on databases of direct molecular interactions. We applied Degree-Aware Disease Gene Prioritization (DADA) to rank the PPI network genes based on their relatedness to a set of OCD candidate genes from two OCD genome-wide association studies (Stewart et al., 2013; Mattheisen et al., 2014). In addition, we performed a pathway analysis with genes from the PPI network. The rate of DN SNVs in OCD was 2.51 × 10(-8) per base per generation, significantly higher than a previous estimated rate in unaffected subjects using the same sequencing platform and analytic pipeline. Several genes harboring DN SNVs in OCD were highly interconnected in the PPI network and ranked high in the DADA analysis. Nearly all the DN SNVs in this study are in genes expressed in the human brain, and a pathway analysis revealed enrichment in immunological and central nervous system functioning and development. The results of this pilot study indicate that further investigation of DN variation in larger OCD cohorts is warranted to identify specific risk genes and to confirm our preliminary finding with regard to PPI network enrichment for particular biological pathways and functions.
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: C
authors.initials: C
authors.lastname: Cappi
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: H
authors.initials: H
authors.lastname: Brentani
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: L
authors.initials: L
authors.lastname: Lima
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Neurogenetics Section, Centre for Addiction and Mental Health, Institute of Medical Science and Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Zai
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: B J
authors.initials: BJ
authors.lastname: Diniz
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: V N S
authors.initials: VN
authors.lastname: Reis
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.|Federal University of São Paulo-UPIA-UNIFESP, São Paulo, Brazil.
authors.forename: A G
authors.initials: AG
authors.lastname: Hounie
authors.affiliation: Federal University of São Paulo-UPIA-UNIFESP, São Paulo, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Conceição do Rosário
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: D
authors.initials: D
authors.lastname: Mariani
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: G L
authors.initials: GL
authors.lastname: Requena
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Puga
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: F L
authors.initials: FL
authors.lastname: Souza-Duran
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: R G
authors.initials: RG
authors.lastname: Shavitt
authors.affiliation: Department of Psychiatry, Harvard Medical School, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Pauls
authors.affiliation: Department of Psychiatry, University of São Paulo School of Medicine, Ovideo Pires de Campos, São Paulo, Brazil.
authors.forename: E C
authors.initials: EC
authors.lastname: Miguel
authors.affiliation: Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: T V
authors.initials: TV
authors.lastname: Fernandez
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D059472:Exome / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D055633:Immune System Phenomena / Q000235:genetics*; D008297:Male; D009154:Mutation; D009420:Nervous System / Q000196:embryology* / Q000254:growth & development; D009771:Obsessive-Compulsive Disorder / Q000235:genetics*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D060066:Protein Interaction Maps / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics