Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33 943 individuals from the general population

While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (∼15-40%) 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 on the 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 (Pfixed = 3.06 ×10−5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 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 (rG = 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. ### Competing Interest Statement David Mataix-Cols receives royalties for contributing articles to UpToDate, Wolters Kluwer Health, outside of the submitted work. Russell J. Schachar has consulted to E. Lilly, Highland Therapeutics and eHave. Henrik Larsson reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; and sponsorship for a conference on attention-deficit/hyperactivity disorder from Shire/Takeda Pharmaceuticals and Evolan Pharma AB, all outside the submitted work. Henrik Larsson is editor-in-chief of JCPP Advances. Paul Arnold receives research funding from Biohaven Pharmaceuticals, unrelated to the submitted work. All other authors report no potential conflict of interest. ### Funding Statement We acknowledge The Swedish Twin Registry (STR) for data access. The STR is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641. The computations/data handling were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppmax partially funded by the Swedish Research Council through grant agreement no. 2018-05973. The Netherlands Twin Register (NTR) warmly thanks all twin families for their participation. NTR is supported by multiple grants from the Netherlands Organizations for Scientific Research (NWO) and Medical Research (ZonMW): Netherlands Twin Registry Repository (NWO 480-15-001/674); the Biobank-based integrative omics study (BIOS) funded by BBMRI-NL (NWO projects 184.021.007 and 184.033.111); the European Science Council (ERC) Genetics of Mental Illness (ERC Advanced, 230374, PI Boomsma); the Royal Netherlands Academy of Science Professor Award (PAH/6635) to D.I.B.; Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1). Part of the genotyping was funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd, the National Institute for Health and Care Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. Spit for Science was supported by the Canadian Institutes of Health Research (R.J.S., MOP‐93696 and P.D.A., MOP‐106573). Dr. Arnold is supported by the Alberta Innovates Translational Health Chair in Child and Youth Mental Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Board of the Karolinska Institutet, Stockholm, Sweden gave ethical approval for the work related to the Swedish Twin Register (reference number 2018/2232-32). The Central Ethics Committee on Research Involving Human Subjects of the VU University Medical Centre, Amsterdam, an Institutional Review Board certified by the U.S. Office of Human Research Protections gave ethical approval of the work related to the NTR (IRB number IRB00002991 under Federal-wide Assurance - FWA00017598; IRB/institute codes, NTR 03-180). The Research Ethics Board at the Hospital for Sick Children gave ethical approval for the work related to the Spit for Science cohort. The ethics committee of The Guys & St Thomas' Trust (GSTT) gave ethical approval for the work related to the TwinsUK study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The meta-analyzed summary statistics will be made available via the Psychiatric Genomics Consortium Download page ().