Modified Project Summary/Abstract Section In this study, I seek to understand how common and rare genetic variation influences the risk of developing obsessive-compulsive disorder (OCD). OCD is a disabling psychiatric disorder with an unclear underlying pathophysiology, which has hindered the development of new treatments and interventions. While there is a clear genetic contribution to OCD risk, decades of investigations have yet to yield reproducible, statistically significant findings that identify high-confidence risk genes. In other neurodevelopmental psychiatric disorders (NDDs), including schizophrenia, attention-deficit/hyperactivity disorder, and autism, genome-wide association studies (GWAS) and whole exome sequencing (WES) in large numbers of subjects are now identifying risk genes and loci, paving the way for novel therapeutics. Increasing sample sizes in OCD and applying multi-omic approaches will lead to similar advances. Of note, in spite of advances in NDDs, studies to date have been primarily carried out in samples of European ancestry (EA), so we know comparatively less about the genetic architecture of these disorders in non-EA populations. To address these gaps, with the ultimate goal of studying the role of common and rare deleterious variation in OCD risk. I will work on emerging, large-scale WES studies in OCD, collaborate in ongoing common variant studies, and collect and analyze Latin American (LA) OCD samples. To achieve these goals, during the K99 phase, I will first be trained on, and make use of, relevant statistical genetic methods using suitably powered samples of autism, schizophrenia, and other psychiatric disorders, while building a LA OCD cohort. The R00 phase will focus on meta-analyses of OCD genetic data, including the LA cohort, using well-established pipelines. This will increase power to identify OCD risk genes and loci and will enable functional approaches using gene findings to study pathways, cell types, and developmental stages implicated in OCD risk. Furthermore, since studies of cross-disorder risk are an opportunity to enhance gene discovery by combining datasets, in the R00 phase shared risk between psychiatric disorders will be leveraged in exploratory analyses in the OCD gene and locus discovery efforts. Ultimately, these efforts will begin with OCD, using genome-wide techniques across populations, and expand into other NDDs.