White matter diffusion estimates in obsessive-compulsive disorder across 1653 individuals: machine learning findings from the ENIGMA OCD Working Group.

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) "OCD vs. healthy controls" (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) "unmedicated OCD vs. healthy controls" (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) "medicated OCD vs. unmedicated OCD" (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6-79.1 in adults; 35.9-63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

The functional connectome in obsessive-compulsive disorder: resting-state mega-analysis and machine learning classification for the ENIGMA-OCD consortium.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Patient adherence as a predictor of acute and long-term outcomes in concentrated exposure treatment for difficult-to-treat obsessive-compulsive disorder.

BACKGROUND: Exposure and response prevention (ERP) is considered the first-line psychotherapy for obsessive-compulsive disorder (OCD). Substantial research supports the effectiveness of ERP, yet a notable portion of patients do not fully respond while others experience relapse. Understanding poor outcomes such as these necessitates further research. This study investigated the role of patient adherence to ERP tasks in concentrated exposure treatment (cET) in a sample who had previously not responded to treatment or relapsed. METHOD: The present study included 163 adults with difficult-to-treat OCD. All patients received cET delivered during four consecutive days. Patients' treatment adherence was assessed using the Patient EX/RP Adherence Scale (PEAS-P) after the second and third day of treatment. OCD severity was evaluated at post-treatment, 3-month follow-up, and 1-year follow-up by independent evaluators. RESULTS: PEAS-P scores during concentrated treatment were associated with OCD-severity at post-treatment, 3-month follow-up, and 1-year follow-up. Moreover, PEAS-P scores predicted 12-month OCD severity adjusting for relevant covariates. Adherence also predicted work- and social functioning at 1-year follow-up. CONCLUSIONS: These results indicate that ERP adherence during the brief period of cET robustly relates to improvement in OCD symptoms and functioning in both the short and long term. Assessing adherence might identify patients at risk of poor outcomes, while improving adherence may enhance ERP for treatment resistant patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02656342.

The effectiveness and acceptability of the Bergen 4-day treatment for adolescents with OCD: a replication and extension.

BACKGROUND: B4DT is a concentrated treatment format with prolonged sessions of exposure and ritual prevention (ERP) delivered over four consecutive days. Two previous open trials demonstrated promising results of the Bergen 4-day treatment (B4DT) for adolescents with obsessive-compulsive disorder (OCD). The aim of the current study was to replicate the initial results with a new sample of adolescents and different therapists at different sites across Norway. METHODS: Forty-three youths participated in treatment program. At pretreatment, posttreatment, and the three-month follow-up, OCD symptoms were assessed using the CY-BOCS interview, while the GAD-7 and PHQ-9 were administered to rate general anxiety symptoms and depressive symptoms. Acceptability and patient satisfaction with the treatment were rated with the CSQ-8. RESULTS: All symptoms were significantly reduced at posttreatment and follow-up. At posttreatment, 36 patients (85.71%) were defined as responders, while 29 patients (69.05%) achieved remission. At the three-month follow-up, 36 patients (92.3%) were defined as responders, while 33 patients (84.62%) were in remission. CSQ-8 scores indicated that the patients were highly satisfied with the treatment. CONCLUSIONS: The B4DT was successfully replicated in a new sample at different sites across Norway, which indicates that this treatment is generalizable, effective and acceptable to adolescents with OCD.

The Bergen 4-day treatment for social anxiety disorder: a pilot study.

BACKGROUND: Few studies have examined the use of concentrated and intensified cognitive behaviour therapy for treating social anxiety disorder (SAD). The aim of this study was to examine the feasibility of the Bergen 4-Day Treatment (B4DT) for treating SAD. METHODS: This study adopted an open trial design without a control group. Thirty consecutively referred patients who were diagnosed with SAD were treated and assessed at pre-treatment, at post-treatment, and at the 3-month follow-up. The Liebowitz Social Anxiety Scale was used to assess symptoms of SAD; the Generalized Anxiety Disorder-7 scale was used to assess anxiety symptoms; and the Patient Health Questionnaire-9 was used to assess symptoms of anxiety and depression. The Client Satisfaction Questionnaire-8 was administered posttreatment. RESULTS: Overall, patients reported a high level of satisfaction with the B4DT. Large effect sizes were observed for symptoms of SAD (d = 1.94-2.66) and for the secondary outcomes, i.e., generalized anxiety (d = 0.86-0.99) and depression (d = 0.62-0.83). The remission rate was 55.2% at follow-up, while the treatment response rate was 89.7%. CONCLUSIONS: The B4DT is a promising treatment approach for patients with SAD. In the future, controlled trials should be performed to compare the efficacy of this treatment approach with standard outpatient treatment. Practical consequences, policy implications, and suggestions for future research are discussed herein.

Is the Conners' continuous performance test helpful for assessing attention deficit hyperactivity disorder in a clinical setting?

BACKGROUND: Despite lacking validation for Norwegian populations, the Conners Continuous Performance Test II (CCPT-II) is applied to almost one-third of children receiving an ADHD diagnosis. However, evidence of the CCPT-II's ability to differentiate between children with and without ADHD is contradictory. Thus, this study examines how CCPT-II results correlate with ADHD symptoms reported by mothers and teachers in a sample representing ordinary child and adolescent mental health services and explores the extent to which the CCPT-II influences the diagnostic result. METHODS: Correlations between CCPT-II results and ADHD Rating Scale scores and a clinical diagnosis of ADHD were analysed in children aged 6-15 years (N = 69) referred to a child and adolescent psychiatric outpatient clinic. RESULTS: Total ADHD symptom scores rated by mothers correlated with hit reaction time (HRT) block change (.260), HRT inter-stimulus interval (ISI) change (.264) and CCPT-II overall index (.263), while hyperactivity subscale scores correlated with omissions (.285), HRT (.414) and variability (.400). In teachers' ratings, total ADHD and both subscale scores correlated with commissions (.280-.382), while hyperactivity scores correlated with variability (.265). A higher number of commissions was the only significant difference in CCPT-II performance between children diagnosed with and children without ADHD. CONCLUSIONS: Correlations between CCPT-II results and ADHD symptoms were all small to moderate. As such, CCPT-II results should be interpreted with caution, because they correspond to a limited degree with other sources of information.

The Bergen 4-day treatment for panic disorder: adapting to COVID-19 restrictions with a hybrid approach of face-to-face and videoconference modalities.

BACKGROUND: The Bergen 4-day treatment (B4DT) is a concentrated exposure-based therapy that has been shown to be effective in the treatment of anxiety disorders. The current study sought to examine the effectiveness of B4DT for panic disorder (PD), when delivered with a combination of face-to-face sessions and videoconferencing. METHODS: Treatment was delivered to 50 patients from April 2020 to May 2021. Because of regulations during the pandemic, a significant portion of the treatment was conducted via videoconference. The primary outcome measure was the clinician-rated Panic Disorder Severity Scale (PDSS), and secondary measures included patient-rated symptoms of panic disorder, agoraphobia, generalized anxiety, depression, and treatment satisfaction. Changes in symptom levels over time were estimated using multilevel models. RESULTS: Patients showed a significant reduction in clinician-rated symptoms of panic disorder (Measured by PDSS) from before treatment to post treatment (d = 2.18) and 3-month follow-up (d = 2.01). At three months follow-up 62% of patients were classified as in remission, while 70% reported a clinically significant response. We also found a reduction in symptoms of depression and generalized anxiety, and the patients reported high satisfaction with the treatment. CONCLUSION: The current study suggests that B4DT delivered in a combination of videoconference and face-to-face meetings may be a useful treatment approach. As the study is uncontrolled, future studies should also include more strictly designed investigations.

The Bergen 4-day treatment for panic disorder: implementation in a rural clinical setting.

INTRODUCTION: The Bergen 4-Day Treatment (B4DT) is a concentrated treatment with individually tailored exposure exercises. The format has shown promising results in the treatment of panic disorder. AIM: The aim of the current study was to investigate the effectiveness of the B4DT in a large sample in a rural clinical setting. METHOD: Fifty-eight patients with panic disorder were consecutively included using an open trial design. The primary outcome measure was the Panic Disorder Severity Scale. The Generalized Anxiety Disorder-7 and the Patient Health Questionnaire-9 were used as secondary outcome measures. Assessments were conducted at pretreatment, posttreatment, and 3-month follow-up. Treatment satisfaction was measured at posttreatment using the Client Satisfaction Questionnaire-8. RESULTS: There was a significant reduction in symptoms of panic disorder from pre- to posttreatment (d = 3.36) and from pretreatment to follow-up (d = 3.63). At posttreatment and follow-up, 72.4% and 81.0% of patients, respectively, were classified as in remission. Patients reported high treatment satisfaction, and there were significant reductions in symptoms of generalized anxiety and depression. CONCLUSION: The results from the current study replicated the findings from previous studies using a larger sample size. The findings indicate that the B4DT is a promising treatment format for panic disorder. The study also demonstrated that the treatment format can be successfully implemented in new rural clinics.

The Bergen 4-day treatment for panic disorder: replication and implementation in a new clinic.

BACKGROUND: Bergen 4-day treatment (B4DT) is a concentrated exposure-based treatment (cET), where the patient receives concentrated, individually tailored cognitive behavioral therapy (CBT) during four consecutive days. Previous findings have indicated that B4DT could be a promising treatment for panic disorder (PD). AIM: The aim of the present study was to evaluate the implementation of B4DT for panic disorder with- and without agoraphobia, at a new clinic. This is the first replication study for B4DT on panic disorder. METHOD: Thirty consecutively recruited patients with PD were included in an open trial design. Assessment of symptoms of panic disorder were measured with Panic Disorder Severity Scale (PDSS), while symptoms of generalized anxiety were assessed by Generalized Anxiety Disorder-7 (GAD-7) and depressive symptoms by Patient Health Questionnaire (PHQ-9) pre-treatment, post-treatment and at 3-month follow-up. Treatment satisfaction was measured with Client Satisfaction Questionnaire (CSQ-8) post-treatment. RESULTS: The results showed a significant reduction in symptom severity from pre-treatment to post-treatment (d = 4.32), and at 3-month follow-up (d = 4.91). The proportion of patients classified as fulfilling the criteria for remission was 80.0% at post-treatment and 86.7% at follow up. There was a significant reduction in symptoms of depression and generalized anxiety. Treatment satisfaction was high and none of the patients dropped out. CONCLUSION: The current study replicated the results from the original study and indicate that the treatment can be successfully implemented at new clinics. B4DT may be a promising treatment for panic disorder and comorbid symptoms of generalized anxiety and depression. Larger and more controlled studies are needed to establish the efficacy of B4DT for panic disorder.

Personality traits and hardiness as risk- and protective factors for mental distress during the COVID-19 pandemic: a Norwegian two-wave study.

BACKGROUND: Several risk factors for anxious-depressive symptomatology during the COVID-19 pandemic have been established. However, few studies have examined the relationship between personality traits, hardiness, and such symptomatology during the pandemic. These constructs might serve as risk- and/or protective factors for such mental distress through the pandemic. METHODS: A sample of 5783 Norwegians responded to a survey at two time points within the first year of the pandemic. The first data collection was in April 2020 (T1) and the second in December 2020 (T2). Measures included the Ten-Item Personality-Inventory, the Revised Norwegian Dispositional Resilience Scale, and the Patient Health Questionnaire Anxiety and Depression Scale. Analyses were performed using Pearson's correlations, multiple linear regression, and a moderation analysis. RESULTS: Anxious-depressive symptomatology in early phases (T1) of the pandemic was the strongest predictor for the presence of such symptomatology 9 months after the outbreak (T2). Personality and hardiness correlated significantly with mental distress at T1 and T2. Personality traits explained 5% variance in symptoms when controlling for age, gender, solitary living, negative economic impact, and mental distress at baseline. Higher neuroticism predicted higher mental distress, whereas higher conscientiousness and extraversion predicted less mental distress. Hardiness did not explain variance in outcome beyond personality traits. Hardiness did not significantly moderate the relationship between neuroticism and mental distress. CONCLUSION: Individuals with high levels of neuroticism had greater difficulties adapting to the circumstances of the COVID-19 pandemic and were more prone to mental distress. Contrastingly, higher conscientiousness and extraversion may have served as protective factors for mental distress during the pandemic. The current findings might aid identification of vulnerable individuals and groups. Consequently, preventive interventions could be offered to those who need it the most.

Mental health symptoms during the first months of the COVID-19 outbreak in Norway: A cross-sectional survey study.

BACKGROUND: The COVID-19 pandemic has led to major social and economic changes that could impact public mental health. The main aim of the current study was to investigate mental health in Norway during the COVID-19 outbreak (since the first confirmed case on 26 February 2020). METHODS: The results are from the first wave of the data collection (1 April-2 June 2020), which took place during the outbreak along with its initial restrictions. A total of 19,372 (11,883 students) people participated in a cross-sectional web-based survey. RESULTS: A total of 21.8% scored above the cut-off for depression and 23.7% for anxiety. Severity of symptoms was associated with the accumulation of risk factors, such as possible/confirmed infection for oneself or one's family, female/other sex, students, having mental health problems, increased use of tobacco, increased use of alcohol, less exercise, losing one's job, suffering economic impact and lower education. CONCLUSIONS: COVID-19 could have a negative association with public mental health, especially for certain risk groups. Future data-collection waves will provide further insight into the development of symptoms following the pandemic.

The Bergen 4-day treatment for OCD: four years follow-up of concentrated ERP in a clinical mental health setting.

There are few long-term follow-up studies on psychological treatment of anxiety disorders carried out in clinical mental health settings, so called effectiveness studies. The present paper presents a four year follow-up of patients with obsessive-compulsive disorder treated by the Bergen 4-day treatment (B4DT), a concentrated form of exposure and response prevention (ERP). A total of 77 obsessive-compulsive disorder (OCD) patients received treatment during four consecutive days and were assessed with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) pre, post, and at follow-ups after 3 and 6 months, and 4 years post-treatment. The Y-BOCS mean score changed from 25.9 at pre- to 10.0 post-treatment and 9.9 at long-term follow-up. The proportion fulfilling the strict international consensus criteria for remission was 73% at post-treatment and 69% at follow-up. When taking declining rate, attrition rate, remission, relapse, and further improvement during the follow-up period into account, 72% were recovered on a long-term basis. A comparison with previously published effectiveness studies of ERP indicated that the 4-day treatment yielded significantly higher proportions of remission at post-treatment and recovery at follow-up, as well as within-group effect size on the Y-BOCS. The implications of these results are discussed.

Successfully treating 90 patients with obsessive compulsive disorder in eight days: the Bergen 4-day treatment.

BACKGROUND: Oslo University Hospital, Norway, had by autumn 2016, accumulated a waiting list of 101 patients with obsessive-compulsive disorder (OCD) who had a legal right to receive treatment by a specialized OCD team. In this challenging situation, the Bergen OCD-team suggested to solve the problem by offering all patients an option for the rapid Bergen 4-day treatment (B4DT). The B4DT is an individual treatment delivered during four consecutive days in a group of six patients with the same number of therapists. The approach has previously shown a post-treatment response rate of 90% and a 3-month remission rate of 70%. METHODS: Ninety-seven of the wait-list patients were available for the scheduled time slots, and 90 received the 4-day format during 8 days (45 patients each week). The therapists were recruited from 22 different specialized OCD-teams from all over Norway, and 44 (68%) had not previously delivered the 4-day format. RESULTS: Post-treatment; 91.1% of the patients were classified as responders, and 72.2% were in remission. At 3-month follow-up; 84.4 were classified as responders and the remission rate was 67.7%. Oslo University Hospital now offers the 4-day treatment as standard treatment for OCD. CONCLUSIONS: We conclude that the B4DT is an acceptable and potentially effective OCD-treatment.

The role of metacognition and obsessive-compulsive symptoms in psychosis: an analogue study.

BACKGROUND: Several studies have indicated that obsessive-compulsive disorder (OCD) is a common comorbidity in patients with psychotic disorders, but there is sparse knowledge about the relationship between symptoms of OCD and psychotic symptoms. Metacognitions which guides thinking and coping is theorized to be a transdiagnostic component central for development and maintenance of psychological disorders, OCD and psychosis included. The aim of the study was therefore to explore how symptoms of OCD and metacognitions relate to symptoms of psychosis. Our main hypotheses were that metacognitions would be significantly related to all symptoms of psychological distress, and that there is considerable overlap between symptoms of psychosis and OCD. METHODS: Community controls (N = 194) completed an internet survey measuring levels of paranoid ideation, predisposition to hallucinations, symptoms of OCD, depression, anxiety, and metacognitions. Correlations and hierarchical multiple linear regression analyses were used to unveil the relationship between symptoms and beliefs. RESULTS: Symptoms of OCD showed a strong positive correlation with symptoms of psychosis, and the relationships were still significant after controlling for symptoms of anxiety and depression. Metacognitions also showed strong positive correlations with all symptom measures. Metacognition and OCD-symptoms accounted for 53.8% of the variance in paranoid ideation and 43.8% of predisposition to hallucinations. There was a large overlap between symptoms of psychosis, OCD-symptoms, and metacognitions (30.2-37.3%). CONCLUSIONS: In general, the results suggest considerable overlap between paranoid ideation, predisposition to hallucinations, and OCD and metacognitive beliefs in a non-clinical sample. Further experimental- and clinical studies are needed in order to explore metacognitive models of OCD and psychosis.

Psychotic and schizotypal symptoms in non-psychotic patients with obsessive-compulsive disorder.

BACKGROUND: Research is scarce with regard to the role of psychotic and schizotypal symptoms in treatment of obsessive-compulsive disorder (OCD). The aim of the current study was to investigate the occurrence and specificity of psychotic and schizotypal symptoms among non-psychotic OCD patients, and to examine whether such symptoms was associated with response to exposure and response prevention (ERP), and whether ERP for OCD had an impact on psychotic and schizotypal symptoms. METHODS: Non-psychotic OCD patients (n = 133) and a general non-psychotic psychiatric outpatient sample (n = 110) were assessed using self-report inventories before and after psychological treatment. RESULTS: Non-psychotic OCD patients did not report greater degree of psychotic or schizotypal symptoms than the control group. Psychotic and schizotypal symptoms were not associated with OCD symptoms before or after ERP. Psychotic and schizotypal symptom were significantly reduced following ERP. CONCLUSIONS: Psychotic and schizotypal symptoms seem to be equally prevalent among non-psychotic OCD patients and non-psychotic psychiatric controls. These symptoms were more linked to depressive symptoms than OCD symptoms. In non-psychotic OCD patients, ERP seems sufficient in reducing OCD symptoms despite the presence of psychotic- and schizotypal symptoms, and reductions in psychotic- and schizotypal symptoms were observed following ERP.

Cognitive behavioural therapy for obsessive-compulsive disorder with comorbid schizophrenia: a case report with repetitive measurements.

BACKGROUND: Obsessive-compulsive disorder (OCD) has been observed in a substantial proportion of patients with schizophrenia. Although cognitive-behavioural therapy (CBT) is well documented for OCD, few case studies are available regarding CBT for comorbid OCD in schizophrenia. AIMS: The study aims to present a case study to augment the limited knowledge concerning CBT treatment for OCD in patients with schizophrenia. METHOD: The research adopted a case study approach, with a baseline condition and repeated assessments during the 3-week treatment and 6-month follow-up period. RESULTS: The treatment was successful and the patient achieved clinical significant change in OCD symptoms. The patient had a reduction on the Y-BOCS from 24 to 5 (79%) and from 38 to 10 (73%) on the OCI-R from before treatment to 6 months follow-up. He did not fulfil the criteria for an OCD diagnosis at the end of the 3-week treatment period, or the follow-up at 3- and 6 months. CONCLUSIONS: The results strengthen the impressions given by previous case studies suggesting that CBT may be a promising treatment for OCD in patients with schizophrenia.

A Burden of Rare Copy Number Variants in Obsessive-Compulsive Disorder.

Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from large, rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2,248 deeply phenotyped OCD cases and 3,608 unaffected controls from Sweden and Norway. We found that in general cases carry an elevated burden of large (>30kb, at least 15 probes) CNVs (OR=1.12, P=1.77×10-3). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02-0.11, P=2.58×10-3). This signal was largely driven by CNVs overlapping protein-coding regions (OR=1.19, P=3.08×10-4), particularly deletions impacting loss-of-function intolerant genes (pLI>0.995, OR=4.12, P=2.54×10-5). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60×10-3). In cases where sufficient clinical data were available (n=1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P<0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P=0.02). The results demonstrate a contribution of large, rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.

Genome-wide association study identifies new loci associated with OCD.

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.