To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28\% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS meta-analysis with a 2-3-fold increase in case sample size (OCD cases: N = 37,015, controls: N = 948,616) compared to the last OCD GWAS, including six previously published cohorts (OCGAS, IOCDF-GC, IOCDF-GC-trio, NORDiC-nor, NORDiC-swe, and iPSYCH) and unpublished self-report data from 23andMe Inc. We explored the genetic architecture of OCD by conducting gene-based tests, tissue and celltype enrichment analyses, and estimating heritability and genetic correlations with 74 phenotypes. To examine a potential heterogeneity in our data, we conducted multivariable GWASs with MTAG. We found support for 15 independent genome-wide significant loci (14 new) and 79 protein-coding genes. Tissue enrichment analyses implicate multiple cortical regions, the amygdala, and hypothalamus, while cell type analyses yielded 12 cell types linked to OCD (all neurons). The SNP-based heritability of OCD was estimated to be 0.08. Using MTAG we found evidence for specific genetic underpinnings characteristic of different cohort-ascertainment and identified additional significant SNPs. OCD was genetically correlated with 40 disorders or traits- positively with all psychiatric disorders and negatively with BMI, age at first birth and multiple autoimmune diseases. The GWAS meta-analysis identified several biologically informative genes as important contributors to the aetiology of OCD. Overall, we have begun laying the groundwork through which the biology of OCD will be understood and described.

中文翻译：

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全基因组关联研究确定了与强迫症相关的新位点

迄今为止，已有四项强迫症 (OCD) 全基因组关联研究 (GWAS) 发表，报告单核苷酸多态性 (SNP) 遗传率为 28%，但仅发现一个显着的 SNP。样本量的大幅增加可能会导致进一步鉴定介导强迫症易感性的 SNP、基因和生物途径。与上次强迫症 GWAS 相比，我们进行了 GWAS 荟萃分析，病例样本量增加了 2-3 倍（强迫症病例：N = 37,015，对照：N = 948,616），其中包括 6 个先前发表的队列（OCGAS、IOCDF- GC、IOCDF-GC-trio、NORDiC-nor、NORDiC-swe 和 iPSYCH）以及来自 23andMe Inc. 的未发表的自我报告数据。我们通过进行基于基因的测试、组织和细胞类型富集分析和估计 74 种表型的遗传力和遗传相关性。为了检查数据中潜在的异质性，我们使用 MTAG 进行了多变量 GWAS。我们发现了对 15 个独立的全基因组重要位点（14 个新）和 79 个蛋白质编码基因的支持。组织富集分析涉及多个皮质区域、杏仁核和下丘脑，而细胞类型分析产生了与强迫症相关的 12 种细胞类型（所有神经元）。基于 SNP 的 OCD 遗传力估计为 0.08。使用 MTAG，我们发现了不同队列确定的特定遗传基础特征的证据，并确定了其他重要的 SNP。强迫症与 40 种疾病或特征存在遗传相关性——与所有精神疾病呈正相关，与 BMI、初生年龄和多种自身免疫性疾病呈负相关。GWAS 荟萃分析确定了几个具有生物学信息的基因是强迫症病因学的重要贡献者。总的来说，我们已经开始为理解和描述强迫症的生物学奠定基础。