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.
Highlights
The etiology of common neuropsychiatric disorders is believed to be multifactorial, with contributions from both environmental and genetic factors.[1]
There was no significant overlap between these same gene lists and lists of risk genes for autism, schizophrenia and intellectual disability[45] (Supplementary Table 10). This is the first reported whole-exome sequencing (WES) study in obsessive-compulsive disorder (OCD) designed to search for rare de novo (DN) single-nucleotide variant (SNV) across all the coding regions of the genome in parent–child trios
As with similar studies in other neuropsychiatric disorders, the DN SNVs we identified may include true OCD risk variants and point toward relevant gene networks and canonical pathways
Summary
The etiology of common neuropsychiatric disorders is believed to be multifactorial, with contributions from both environmental and genetic factors.[1]. A substantial portion may reflect gene–gene interactions and gene–environmental interactions that have not been taken into consideration in estimates of narrow sense heritability.[3] In addition, understanding the heritability of genetic diseases requires a more comprehensive assessment of human genetic variation, including rare variation, throughout the genome.[3,4]. The emergence of next-generation sequencing platforms is facilitating comprehensive searches for both rare and common single-nucleotide variants (SNVs) across all genes in the genome via whole-exome sequencing (WES).[5] protein-coding genes constitute only about 1% of the human genome, they are estimated to harbor 85% of mutations with large effects in disease-related traits.[6]
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