Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nat Neurosci. 2021 Aug;24(8):1071-1076. doi: 10.1038/s41593-021-00876-8. Epub 2021 Jun 28.
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). 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). These data support a contribution of rare coding variants to OCD genetic risk.
强迫症（OCD）影响 1-2%的人口，与其他复杂的神经精神障碍一样，人们认为罕见的变异会增加其遗传风险。在这项研究中，我们对迄今为止最大的 OCD 队列进行了外显子组测序（共有 1313 例病例，包括 587 个三核苷酸、41 个四核苷酸和 644 个单核苷酸），并描述了罕见的有害编码变异对疾病风险的贡献。在病例对照分析中（n=1263/11580），最显著的单基因结果是在 SLITRK5 中观察到（比值比（OR）=8.8，95%置信区间 3.4-22.5，P=2.3×10）。在整个外显子组中，在 LoF 不耐受基因中，特异性地存在 LoF 变异的过度缺失（OR=1.33，P=0.01）。在对三核苷酸的分析中，我们观察到相对于对照组，新生错义预测有害变异的过度出现（OR=1.22，P=0.02），以及 LoF 不耐受基因中新生 LoF 突变的过度出现（OR=2.55，P=7.33×10）。这些数据支持罕见编码变异对 OCD 遗传风险的贡献。
