Rare coding mutations identify 36 large-effect risk genes in obsessive-compulsive disorder and chronic tic disorders

Obsessive-compulsive disorder (OCD) and chronic tic disorders (CTD) are highly heritable. Recent progress in OCD genomics has highlighted small-effect common alleles. Rare mutations have previously been found to carry large risks for OCD and CTD but only four high-confidence (hc) genes have been identified. We analyzed whole-exome sequencing data from 3,964 individuals with OCD, CTD, or both, including 2,418 trios. We find an excess in cases of de novo and rare protein-damaging mutations and identify 36 hc genes (false discovery rate [FDR] < 0.1), four of which overlap with OCD GWAS loci. Risk genes are shared among OCD, CTD, autism spectrum disorder, and other neurodevelopmental conditions. Transcriptomic and network analyses highlight mechanistic convergence and increased risk gene expression in postnatal cerebellum and pre- and postnatal cortex and striatum. Dozens of large-effect OCDCTD genes offer insights into pathogenesis and a path forward for illuminating pathophysiology and identifying novel treatment targets.