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.

目前关于强迫症 （OCD） 的遗传研究支持常见的单核苷酸变异 （SNV） 以及罕见的编码 SNV 和小插入缺失 （indel） 对风险的贡献。然而，罕见拷贝数变异 （CNV） 对 OCD 风险的贡献尚未以类似的规模进行正式评估。在这里，我们描述了对来自瑞典和挪威的 2248 例深度表型强迫症病例和 3608 例未受影响的对照中的基因型阵列数据中调用的罕见 CNV 的分析。病例的 CNV 负担增加 ≥ 30 kb 大小 （OR = 1.12，P = 1.77 × 10⁻³）。与对照组相比，病例中这些 CNV 的超额率约为 0.07 （95% CI 0.02-0.11，P = 2.58 × ^10-3）。该信号主要由重叠蛋白质编码区的 CNV 驱动 （OR = 1.19，P = 3.08 × ^10-4），特别是影响功能丧失不耐受基因的缺失 （pLI >0.995，OR = 4.12，P = 2.54 × ^10-5）。我们没有确定 CNV 负担与 OCD 病例状态在全基因组显著性上相关的任何特定位点，但我们注意到病例中 CNV 缺失的非随机复发（排列 P = 2.60 × 10⁻³）。在有足够临床数据的情况下 （n = 1612），我们发现神经发育重复的携带者更有可能患有自闭症 （P < 0.001），并且缺失重叠神经发育基因的携带者治疗反应较低 （P = 0.02）。结果表明罕见的 CNV 对 OCD 风险有贡献，并表明如果将这类变异纳入正式测试，对 OCD 中罕见编码变异的研究将具有更强的识别风险基因的能力。