RARE AND DE NOVO VARIANTS IN OBSESSIVE COMPULSIVE DISORDER

Background Obsessive Compulsive Disorder (OCD) is a complex neuropsychiatric disorder that affects approximately 1% of the population. It is likely that the genetic architecture underlying the disorder is complex, and that furthermore some subset of it involves rare and de novo variants of relatively large effect size. Methods We have generated what to our knowledge is the largest high throughput sequencing dataset for this disorder presently in existence. The data consist of over 550 sporadic OCD trios and quartets selected for whole exome sequencing, as well as 150 representative affected members of multiplex families for OCD that were selected for whole genome sequencing. We have carried out an analysis of rare and de novo coding variation within this cohort in order to assess how much it contributes to OCD risk, as well as if there are any single genes with exome-wide significant levels of damaging variant burden. Results In assessing de novo mutation burden in trios, while we don’t observe a marked departure in mutation rate from what is expected, we do note an elevation of damaging de novo variant burden in cases relative to controls (odds ratio=1.3, p=0.097), as well as in individuals with an early age at onset (e.g., Discussion In general, the sequence data we have generated provides further support for a complex genetic architecture in OCD, as well as the need for a larger number of samples for adequate resolution.