A burden of rare copy number variants in obsessive-compulsive disorder

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2248 deeply phenotyped OCD cases and 3608 unaffected controls from Sweden and Norway. Cases carry an elevated burden of CNVs ≥30 kb in size (OR = 1.12, P = 1.77 × 10⁻³). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02–0.11, P = 2.58 × 10⁻³). This signal was largely driven by CNVs overlapping protein-coding regions (OR = 1.19, P = 3.08 × 10⁻⁴), particularly deletions impacting loss-of-function intolerant genes (pLI >0.995, OR = 4.12, P = 2.54 × 10⁻⁵). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60 × 10⁻³). In cases where sufficient clinical data were available (n = 1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P < 0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P = 0.02). The results demonstrate a contribution of rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.