Genomics of OCD in Latin American Communities

Rutgers Biomedical And Health Sciences, Newark NJ

Investigators

Abstract

PROJECT SUMMARY 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 condition with unclear pathophysiology, which has hindered the development of effective treatments and interventions. Although there is strong evidence of genetic contribution to OCD risk, decades of research have not yet produced reproducible, statistically significant findings that identify high-confidence risk genes. In contrast, other neurodevelopmental psychiatric disorders (NDDs)—including schizophrenia, attention-deficit/hyperactivity disorder (ADHD), and autism—have seen major advances through genome-wide association studies (GWAS) and whole-exome sequencing (WES) in large samples. These efforts have identified risk loci and genes, paving the way for novel therapeutic targets. Similar progress in OCD is expected as sample sizes increase and multi-omic approaches are applied. However, most existing OCD studies have focused on individuals of European ancestry (EA), limiting generalizability and our understanding of genetic risk in diverse populations. Expanding studies to include globally diverse populations is essential for comprehensive risk gene discovery. Such inclusion facilitates finemapping through differences in allele frequency, enables the investigation of recent rare and ancient functional alleles that may be absent in EA cohorts, and allows examination of complex inheritance patterns such as compound heterozygosity and digenic/oligogenic models. These approaches are vital to advancing our understanding of psychiatric disease biology. To address this gap—and with the ultimate goal of identifying the role of common and rare deleterious variants in OCD—I will analyze rare and common genetic variation in OCD samples, building on prior work during the K99 phase, during which I collected 380 Latin American ancestry (LA) OCD trios. These will be combined with 150 trios from the Rutgers Center for Genomics of Psychiatric Health, totaling 530 trios for this project. The main objectives are to: a) Identify OCD risk genes impacted by rare deleterious variants via meta-analyses with OCD case-control data from the LATINO study; b) Identify OCD risk genes impacted by common variation using ancestry-informed GWAS; and c) Contribute all data to the Psychiatric Genomics Consortium (PGC) OCD Working Group and LATINO consortium to enhance statistical power and fine-mapping of risk loci. While previous OCD studies have largely relied on broad case-control comparisons, this proposal will integrate genomic data from trios with clinical and environmental variables—such as trauma exposure, treatment history, and geolocation—to uncover gene-environment interactions and modifiers of genetic risk. These analyses will move beyond diagnostic categories, allowing for phenotype refinement and the identification of biologically meaningful dimensions of heterogeneity. Finally, we will begin exploratory work to evaluate whether OCD risk genes converge with cortical structural alterations and transcriptomic profiles, contributing to a deeper neurobiological understanding of OCD