Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating disorder.

中文翻译：

---

全基因组关联研究确定了 30 个与强迫症相关的位点

强迫症 (OCD) 影响约 1% 的人口，并表现出较高的 SNP 遗传力，但之前的全基因组关联研究 (GWAS) 对该疾病的遗传病因和潜在生物学机制提供的信息有限。我们对来自 28 个欧洲血统队列的 53,660 个强迫症病例和 2,044,417 个对照进行了 GWAS 荟萃分析，揭示了 30 个独立的全基因组显着 SNP，以及基于 SNP 的遗传率为 6.7%。针对临床、生物样本库、共病和自我报告亚组的单独 GWAS 没有发现样本确定影响我们结果的证据。基于功能和位置 QTL 基因的方法确定了 249 个与 OCD 相关的显着候选风险基因，其中 25 个被确定为推定因果基因，突出显示了 WDR6、DALRD3、CTNND1 和 MHC 区域中的基因。组织和单细胞富集分析强调了海马和皮质兴奋性神经元，以及含有 D1 和 D2 型多巴胺受体的中等多棘神经元，在强迫症风险中发挥着作用。强迫症与 112 个检查表型中的 65 个表现出显着的遗传相关性。值得注意的是，它与所有包括的精神表型，特别是焦虑、抑郁、神经性厌食症和抽动秽语综合症，显示出正的遗传相关性，并且与所包括的自身免疫性疾病、受教育程度和体重指数的子集呈负相关。这是朝着揭示其遗传景观和增进对强迫症遗传学的理解迈出的重要一步，为未来解决这种使人衰弱的疾病的干预措施奠定了基础。