Obsessive-compulsive disorder (OCD) is a prevalent neurodevelopmental disorder in the general population, ranked among the 10 most debilitating disorders of any kind, in terms of lost earnings and diminished quality of life. OCD is a familial condition, with first-degree relatives of OCD probands being ~4-5 times more likely to have OCD themselves, compared to relatives of unaffected controls, and disease severity is much greater when the disease-onset is before age 15. Current pharmacological and psychotherapeutic treatments can benefit 60-70% of patients, though many cases are refractory to treatment. The fundamental challenge in identifying novel therapeutic targets is our limited understanding of the underlying genetic architecture and biological mechanisms underlying OCD risk. The genetic contribution to OCD risk is clear, however decades of linkage and common variant candidate association studies have yielded no reproducible associations, and have therefore provided little insight into disease biology. Further efforts are critically needed to identify specific OCD risk genes and pathways by modern genome-wide and comprehensive variant discovery approaches. Our central hypothesis is that families with multiple affected OCD cases are a rich source of rare high-risk (high-penetrant) variants facilitating the identification of risk genes for OCD related with compulsive behavior. Moreover, complementary studies looking at other conditions that exhibit similar compulsive behavior, such as autism spectrum disorders (ASD), may provide an additional source of risk genes shared among OCD and ASD. Indeed, our recent studies of simplex OCD families (Cappi et al. 2017, submitted) suggest genetic overlap among OCD and ASD, where genes harboring rare damaging variants in OCD are enriched for those reported in ASD. Additional studies in multiplex families are now critical to further understand the genetic basis of OCD, find more risk genes, and offer insights on the overlap with ASD. Hence, this proposal aims to investigate rare high-risk (high-penetrant) variation in a unique resource of 10 deeply-phenotyped multiplex OCD families with at least 3 generations of affected individuals or more than 3 affected in the family (totaling 83 individuals). Whole-exome sequencing will be conducted on a subset of informative individuals, and rare high-risk variants will be identified by filtering against large-scale population datasets to remove standing variation, followed by segregation analysis and gene-burden analysis. Additionally, we will compare our results with those of ASD trios with co-occurring OCD as part of ongoing sequencing studies at the host laboratory. The study proposed here will focus on rare damaging variants within the exome because they have the largest effect sizes, can be more readily linked to biology (vs intronic or intergenic variants), and our previous studies have shown that detection of these variants in parent-child trios is a clear path toward identification of high-confidence OCD risk. No studies using this approach have yet been conducted in OCD thus far.
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