1/2 Trans-ancestry genomic analysis of obsessive-compulsive disorder

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PROJECT SUMMARY In this study we seek to understand how genetic factors influence the risk of developing obsessive-compulsive disorder (OCD) in Latin American individuals. OCD and related disorders are of major public health importance owing to their profound personal and societal costs. Little is known for certain about their etiology, and treatment, detection and prevention strategies are not optimal or directed by knowledge of pathophysiology. In other psychiatric disorders (e.g., schizophrenia, bipolar disorder, and autism), genomics has begun to deliver fundamental knowledge about genetic architecture, identify specific loci for biological follow-up and localize pathways altered in disease. We intend to realize these same advances for OCD by markedly increasing and diversifying the worldwide sample size for genomic analysis, in a first step toward elucidating the fundamental biology of this condition. Three overlapping areas will be investigated in this project. First, we will collect the world’s largest ancestrally- diverse sample of OCD cases (N = 5,000 individuals from Latin America). To do this in an efficient and cost- effective manner, we will take advantage of a network of OCD clinics we have established across Latin America, in addition to clinics in the USA and web-based recruitment. The phenotypic data collected will include a detailed clinical characterization including comorbidities and OCD symptom dimensions. Second, we will genotype all 5,000 samples on the Illumina Global Screening Array (genotypes for >10,000 matched controls will be available). This will allow us to, in collaboration with the Psychiatric Genomics Consortium, discover genomic loci harboring common variation associated with OCD. Third, we will fine-map genome-wide significant loci and calculate individual polygenic risk scores (PRS) as a measure of genetic liability to OCD. We expect the new inclusion of ancestrally diverse samples to improve our fine-mapping ability, to yield more accurate PRS in non-European samples and ultimately to reduce health disparities when OCD genomic findings are used clinically. Overall, this study will improve our understanding of the causal mechanisms implicated in OCD, with a view towards improving clinical outcomes and reducing chronicity and societal costs.