Following these previous studies in other disorders and our pilot study suggesting a role for de novo single nucleotide variants (SNVs) in OCD risk (31), we performed whole-exome sequencing (WES) in 222 OCD parent-child trios to identify de novo SNVs and insertion-deletion variants (indels). In 184 OCD trios passing quality control, we find strong evidence for the contribution of de novo likely gene disrupting (LGD; creation or loss of a stop codon, canonical splice site, or a frameshift indel) as well as predicted damaging missense (Mis-D) variants to OCD. Furthermore, we identify two high-confidence candidate risk genes based on observing gene-level recurrence of de novo damaging (LGD + Mis-D) variants in unrelated probands: CHD8 (Chromodomain Helicase DNA Binding Protein 8) and SCUBE1 (Signal Peptide, CUB Domain And EGF Like Domain Containing 1). We estimate that 22% of OCD cases will harbor a de novo damaging SNV or indel mediating OCD risk, and that there are approximately 335 genes affected by such variants contributing to the risk. Finally, we detect significant overlap between genes with damaging de novo variants in OCD and those previously reported in Tourette’s disorder and autism.
