Genomics of OCD in Latin American Communities

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Project Summary/Abstract In this study I seek to understand how common and rare genetic variation influence the risk of developing obsessive-compulsive disorder (OCD). OCD is a disabling psychiatric disorder with as yet 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 in OCD. Of note, in spite of the advances in NDDs, studies to date were 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 Latinx 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 and other psychiatric disorders, while building a Latinx OCD cohort. The R00 phase will focus on meta-analyses of OCD genetic data, including the Latinx 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, I plan to obtain a tenure-track faculty position and launch a laboratory that focuses on the integration of genetics and neurobiological approaches, to discover mechanisms underlying NDDs. These efforts will begin with OCD, using genome-wide techniques and leveraging admixed and diverse populations, and expand into other NDDs. I will also use the K99 phase to deepen knowledge in writing manuscripts and grants, and to improve skills in presenting complex studies to both mixed and specialty audiences.