Rare coding variation in OCD implicates shared genes with other psychiatric disorders.

Importance: Obsessive-compulsive disorder (OCD) affects 2-3% of the population with often disabling obsessions and compulsions. Despite its high heritability, genetic studies of OCD have lagged other psychiatric disorders, particularly in understanding the role of rare genetic variants. Objective: To identify rare coding genetic variants contributing to OCD risk and examine genetic overlap with chronic tic disorders (CTD) and other psychiatric conditions. Design: Family-based and case-control whole-exome sequencing (WES) study. Settings: WES data were aggregated from 11 independent cohorts across Sweden, the United States, and the United Kingdom. Participants: A total of 47,194 individuals were available, and 44,089 passed quality control for analysis. The final sample included 6,071 individuals with OCD, comprising 1,202 probands from family-based trios and 4,869 cases, and 38,018 controls. Exposures: Rare damaging coding variants identified by WES. Main Outcomes and Measures: Identification of OCD risk genes through rare variant analyses, meta-analysis with CTD data, gene-set enrichment analyses, and evaluation of cross-disorder genetic overlap using curated gene sets. Results: The analysis provided an estimate of approximately 470 autosomal genes contributing to OCD risk through rare genetic variation. Conclusions and Relevance: In this largest study to date of rare coding variation in OCD, we confirm