Exome sequencing in obsessive–compulsive disorder reveals a burden of rare damaging coding variants

Obsessive–compulsive disorder (OCD) affects 1–2% of the population, and, as with other complex neuropsychiatric disorders, it is thought that rare variation contributes to its genetic risk. In this study, we performed exome sequencing in the largest OCD cohort to date (1,313 total cases, consisting of 587 trios, 41 quartets and 644 singletons of affected individuals) and describe contributions to disease risk from rare damaging coding variants. In case–control analyses (n = 1,263/11,580), the most significant single-gene result was observed in SLITRK5 (odds ratio (OR) = 8.8, 95% confidence interval 3.4–22.5, P = 2.3 × 10−6). Across the exome, there was an excess of loss of function (LoF) variation specifically within genes that are LoF-intolerant (OR = 1.33, P = 0.01). In an analysis of trios, we observed an excess of de novo missense predicted damaging variants relative to controls (OR = 1.22, P = 0.02), alongside an excess of de novo LoF mutations in LoF-intolerant genes (OR = 2.55, P = 7.33 × 10−3). These data support a contribution of rare coding variants to OCD genetic risk. An analysis of the largest exome sequencing dataset of people with obsessive–compulsive disorder to date (n = 1,313 affected individuals), where both case–control and de novo variant studies support a contribution of rare damaging coding variants to risk.