DESCRIPTION (provided by applicant): The wealth of information provided by whole-exome and whole-genome sequencing studies can make it difficult to pick out the variants that cause disease. Family sequencing, in particular the sequencing of trios and quartets with affected children and unaffected parents, allows one to remove most of the rare variants that are present in the genome and focus on those few that are de novo or rare and homozygous only in the offspring. There is growing recognition that this is an important method in the study of complex diseases. Here, we propose to perform whole- exome sequencing in families to identify genetic variants predisposing to obsessive compulsive disorder (OCD). OCD is among the 10 most disabling medical conditions worldwide and involves persistent, intrusive, senseless thoughts and impulses (obsessions) and repetitive, intentional behaviors (compulsions). The lifetime prevalence of OCD is estimated at 1-3%. Although medication and behavioral therapy, available since the late 1980s, are useful, they control symptoms with only limited success, and the course of the condition remains chronic in most cases; cure is rare. It is therefore critical to understand the pathophysiology of OCD so we can ultimately develop effective treatments. We will sequence the exomes of 375 simplex OCD trios and 100 OCD quartets comprising affected sibs and unaffected parents. In the trios, we will identify de novo variants that are annotated as functional. Even if de novo variants are found to explain a small proportion of OCD cases, the general rarity of de novo variants that are annotated as functional should facilitate the discovery of causal de novo variants when they exist. Furthermore, the sequencing of trios (and quartets) allows for the identification of causal variants that are homozygous or compound heterozygous in the offspring but heterozygous in the parents. We will identify candidate variants falling into these categories and will prioritize them based upon functional annotation, rarity and overlap of implicated genes between unrelated families. We will then confirm these variants by genotyping them in unaffected family members. Finally, we will look for characteristics that are shared between unrelated cases with causal variants in the same gene.

PUBLIC HEALTH RELEVANCE: OCD is among the 10 most disabling medical conditions worldwide, with a lifetime prevalence of 1-3%. The currently available medication and behavioral therapy are useful, but they control symptoms with only limited success, and the cure of OCD is rare. Here, we will use perform whole-exome sequencing on families with OCD to identify the genetic variants influencing this condition. The discovery of such variants will help us to understand the pathophysiology of OCD, leading ultimately to the development of effective treatments.