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.

From Protein Variations to Biological Processes and Pathways with NET-GE

“…Our results highlight the involvement of processes common to the gene panel and corroborates the notion that network-based enrichment consistently derives information from the connected annotation modules, including genes corresponding to 9 of the 14 patients analyzed in [18].…”

“…Function (panel B). Genes are derived from [18]. Terms highlighted with a double star are new annotations, not associated to the input proteins and enriched with the network-based procedure.…”

“…Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric disorder characterized by the presence of obsessions and compulsions [18]. This disorder has been recently investigated in [18] by using whole-exome sequencing (WES).…”

“…Based on Ingenuity software (https://www.qiagenbioinformatics.com/products/ ingenuity-pathway-analysis), three signaling pathways were identified as disease-related [18] sharing only one patient/one gene. In fact, among the 27 genes, only SMAD4 (gene mutated in only one patient) was present in the three enriched pathways.…”

Relation between executive functions and polymorphisms in COMT, MAO-A, HTTLPR, SLC1A1 and HT2A in a sample of children with Obsessive Compulsive Disorder

“…Miguel et al (2005) state that variability in the phenotypic expression has led to the hypothesis that OCD is a heterogeneous disorder that obscures clinical findings, the natural history of the disease, the response to treatment and the search for related genes. Current research on OCD is directed to describe such heterogeneity in order to improve its clinical and physiological classification by including molecular and anatomical aspects (Browne et al, 2014;Cappi et al, 2016;Grunblatt et al, 2014;Katerberg et al, 2010;Mataix et al, 2008;Orefici et al, 2016;Taylor, 2016;van de Vondervoort et al, 2016).…”