While 1–2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13–38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (P_fixed = 3.06 × 10⁻⁵). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (N_genes = 28, Beta = 0.79, SE = 0.16, P_bon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33–43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (r_G = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.

虽然 1-2% 的人符合强迫症 (OCD) 的临床诊断标准，但更多人 (~13-38%) 在一生中经历过亚临床强迫症 (OCS)。为了描述 OCS 的遗传基础及其与 OCD 的遗传关系，我们对父母或自我报告的 OCS 进行了迄今为止最大规模的全基因组关联研究 (GWAS) 荟萃分析（N  = 33,943，具有完整的表型和全基因组范围）数据），结合了来自瑞典、荷兰、英国和加拿大的七个大规模人群队列的结果（包括六个双胞胎队列和一组不相关的个​​体）。我们发现单核苷酸多态性 (SNP) 或基因水平上没有全基因组显着关联，但基于精神病遗传学联盟 (PGC-OCD) 先前发布的 OCD GWAS 的多基因风险评分 (PRS) 显着相关使用 OCS（P_固定 = 3.06 × 10 ⁻⁵）。此外，一组精选基因（Mootha 糖异生）达到了 Bonferroni 校正显着性（N_基因 = 28，Beta = 0.79，SE = 0.16，P _bon  = 0.008）。这组基因的表达在胰岛素介导的葡萄糖处理位点很高。先前的一项研究描述了 OCS 与儿童和青少年胰岛素信号相关特征的遗传重叠，表明 OCS 病因学中的胰岛素信号失调。我们 在 GWAS 荟萃分析中报告 SNP 遗传率为 4.1%（P = 0.0044），基于双胞胎队列的遗传力估计为 33-43%。遗传相关分析表明， 在所有测试的精神疾病中，OCS 与 OCD 的相关性最强（r _G  = 0.72，p = 0.0007）（ N  = 11）。在所有 97 个测试的表型中，24 个显示出与 OCS 显着的遗传相关性，66 个性状显示出与 OCS 和 OCD 的影响方向一致。 OCS 具有显着的多基因贡献，并且与诊断出的 OCD 具有共同的遗传风险，这支持了以下假设：OCD 代表了人群中广泛分布的 OCS 的极端情况。