Project Summary Obsessive-compulsive disorder (OCD) is a life-long, serious psychiatric disorder that affects 2-3% of the population and is associated with high personal and societal costs. Genetic factors are undoubtedly important in the etiology in OCD, and associated loci and genes are just beginning to be discovered. Studies by us and by others have shown that rare and ultra-rare variation, the latter including recent variation, plays an important role in risk for OCD. In ongoing sequencing studies, we are identifying genes impacted by such variation, using samples collected by the investigators in this application. In this proposal, we take an important new direction to address a critical gap in OCD research by recruiting subjects of self-reported African ancestry (African-American; AA), a group poorly represented in OCD research and not previously represented in OCD genetic research. In fact, AA individuals with OCD are vastly underrepresented, or altogether absent, from treatment centers and research studies, in spite of the evidence for 1) disparities in access to treatment, 2) persistent OCD due to lack of treatment, and, 3) differences in OCD subtypes in AA populations, as well as, 4) Covid-19 pandemic amplified mental-health disparities (including OCD and anxiety disorders). In this proposal, we will systematically investigate the phenotypes of OCD in AA populations, and use high-throughput sequencing to identify rare single nucleotide variation (SNV), insertions/deletions (indels), and structural variation (SV) contributing to OCD susceptibility in this population. To further our understanding of OCD in AA populations we propose the following Specific Aims: 1) To recruit at least 1,250 African American OCD participants and compare phenotypic findings and genetic architecture across ancestries; and, 2) to carry out genetic association studies for ultra-rare variants in the African American cohort and across ancestries. With this new research we will accelerate our overall objective, which is the identification of OCD genes across diverse populations, thereby facilitating our long-term goal of building the foundation from which therapeutic targets for OCD emerge. Our rationale is that the identification of genes conferring significant risk to OCD and associated disorders can form the basis of studies to understand pathogenesis, as well as the basis for novel therapies. Our central hypothesis – formulated based on recent results – is that rare genetic variation contributes significantly to risk of OCD, with certain rare variants conferring substantial risk. The research proposed is innovative, in our opinion, because it uses groundbreaking and novel statistical methods for identifying risk variants for OCD in AA populations, involving a systematic effort to investigate OCD genetic architecture across populations. The research will increase the number of known OCD genes, expand our knowledge of networks and pathways that are disrupted in ...