Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways

Author(s):Show less -

Cappi, C. ^[1] ; Brentani, H. ^[1] ; Lima, L. ^[1] ; Sanders, S. J. ^[2] ; Zai, G. ^{[3, 4]} ; Diniz, B. J. ^[1] ; Reis, V. N. S. ^[1] ; Hounie, A. G. ^{[1, 5]} ; Conceicao do Rosario, M. ^[5] ; Mariani, D. ^[1] ; Requena, G. L. ^[1] ; Puga, R. ^[1] ; Souza-Duran, F. L. ^[1] ; Shavitt, R. G. ^[1] ; Pauls, D. L. ^[6] ; Miguel, E. C. ^[1] ; Fernandez, T. V. ^{[7, 8]}

Affiliation

^[1] Univ Sao Paulo, Sch Med, Dept Psychiat, Sao Paulo - Brazil

^[2] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA - USA

^[3] Univ Toronto, Dept Psychiat, Toronto, ON - Canada

^[4] Univ Toronto, Inst Med Sci, Neurogenet Sect, Ctr Addict & Mental Hlth, Toronto, ON - Canada

^[5] Fed Univ Sao Paulo UPIA UNIFESP, Sao Paulo - Brazil

^[6] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Ctr Human Genet Re, Boston, MA 02115 - USA

^[7] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 - USA

^[8] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT - USA

• Document type: Journal article
• Source: TRANSLATIONAL PSYCHIATRY; v. 6, MAR 29 2016.
• Web of Science Citations: 11

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 x 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. (AU)

• FAPESP's process: 11/14658-2 - Copy number variation in genome of patients with obsessive-compulsive disorder and autism spectrum disorder with restricted interests and repetitive behaviors
• Grantee: Helena Paula Brentani
• Support Opportunities: Regular Research Grants
• FAPESP's process: 08/11537-7 - Copy number variation in the genome of patient with obsessive compulsive disorder
• Grantee: Carolina Cappi
• Support Opportunities: Scholarships in Brazil - Doctorate