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.

Altered Error Monitoring and Decreased Flanker Task Accuracy in Pediatric Obsessive-Compulsive Disorder.

The error-related negativity (ERN) and error positivity (Pe) are components of the event-related potential following an error that are potential mechanistic biomarkers of obsessive-compulsive disorder (OCD). The study examined the ERN, Pe, flanker task accuracy, and clinical measures in 105 OCD cases and 105 matched healthy controls (HC) ages 8-18 years. Higher flanker task accuracy in all participants was associated with an increased ERN amplitude and increased difference between Pe and correct positivity amplitudes (ΔPe). Compared to HC, OCD cases had an increased ERN but decreased ΔPe and flanker task accuracy. Those differences were also significant in tic-related and non-tic-related OCD cases compared to HC. A lower ΔPe was associated in cases with an earlier age at OCD symptom onset. The results support the hypothesis that OCD involves defects in an error monitoring system and suggest a reduced ΔPe may compromise error signaling and cause uncertainty about the correctness of a response.

A Diagnostic Biomarker for Pediatric Generalized Anxiety Disorder Using the Error-Related Negativity.

The error-related negativity (ERN) is a negative deflection in the event-related potential following a mistake that is a putative biomarker of anxiety. The study assessed the ERN as a diagnostic biomarker using receiver operating characteristic (ROC) analyses in 96 cases with anxiety disorders (AD) and 96 matched healthy controls (HC) ages 8 to 18 years. Forty-one cases had generalized anxiety disorder (GAD); 55 cases had other anxiety disorders (OAD) without GAD. ERN amplitude was significantly increased in AD cases compared to HC. The area under the curve (AUC) in the ROC analysis was 0.64, indicating the ERN is an inadequate diagnostic test for AD altogether. The ERN was significantly increased in cases with either GAD or OAD compared to HC. The AUC in ROC analyses with GAD and OAD was 0.75 and 0.56, respectively, suggesting the ERN provides an adequate diagnostic test for GAD but not for OAD.

Screening for Pediatric Obsessive-Compulsive Disorder Using the Obsessive-Compulsive Inventory-Child Version.

The study assessed the ability of the Obsessive-Compulsive Inventory-Child Version (OCI-CV) to detect pediatric obsessive-compulsive disorder (OCD) using receiver operating characteristic analyses. The sample consisted of 114 cases with current OCD, 340 cases with other psychiatric disorders (OPD), and 301 healthy controls (HC) ages 7 to 18 years. All 755 participants were assessed with two semi-structured interviews and seven rating scales. In a comparison of current OCD cases and all other participants, the optimal OCI-CV cut-score was 11 with an area under the curve (AUC) of .88. In a comparison of current OCD cases and OPD cases, the optimal OCI-CV cut-score was 11 with an AUC of .82. In a comparison of current OCD cases and HC, the optimal OCI-CV cut-score was 10 with an AUC of .94. The results indicate that the OCI-CV provides an effective screen for pediatric OCD using empirically derived cut-scores.

Error-related brain activity in adolescents with obsessive-compulsive disorder and major depressive disorder.

BACKGROUND: The error-related negativity (ERN) is a negative deflection in the event-related potential following a mistake that is often increased in patients with obsessive-compulsive disorder (OCD). The relationship of the ERN to comorbid major depressive disorder (MDD) has not been examined in adolescents with OCD. This study compared ERN amplitudes in OCD patients with MDD (OCD + MDD), OCD patients without MDD (OCD - MDD), MDD patients, and healthy controls (HC). METHOD: The ERN, correct response negativity, and accuracy were measured during a flanker task to assess performance monitoring in 53 adolescents with a lifetime diagnosis of OCD, 36 adolescents with a lifetime diagnosis of MDD, and 89 age-matched HC of 13-18 years. Fourteen OCD patients had a history of MDD. RESULTS: ERN amplitude was significantly increased in OCD patients compared to HC and significantly correlated in OCD patients with age at OCD symptom onset, particularly in the OCD - MDD patients. The ERN was significantly enlarged in OCD + MDD patients compared to HC, but not in MDD patients compared to HC. There was a trend for an increased ERN amplitude in OCD - MDD patients compared to HC. OCD patients were significantly less accurate than either MDD patients or HC. CONCLUSIONS: An enlarged ERN is a neural correlate of adolescent OCD that is associated with age at OCD symptom onset. Adolescents with OCD may have impaired cognitive control on a flanker task. Follow-up studies with larger samples may determine whether an enlarged ERN in adolescents with OCD is associated with a higher risk for MDD.

Altered relationship between electrophysiological response to errors and gray matter volumes in an extended network for error-processing in pediatric obsessive-compulsive disorder.

Pediatric patients with obsessive-compulsive disorder (OCD) show an increased electrophysiological response to errors that is thought to be localized to the posterior medial prefrontal cortex (pMFC). However, the relation of this response, the error-related negativity (ERN), to underlying brain structures remains unknown. In an examination of 20 pediatric OCD patients and 20 healthy youth, we found that more negative ERN amplitude was correlated with lower gray matter (GM) density in pMFC and orbital frontal cortex. The association of the ERN with pMFC gray matter volume was driven by the patient group. In addition, a group difference in the association of ERN with gray matter in right insula was observed, showing an association of these measures in healthy youth (more negative ERN amplitude was associated with lower GM density in insula), but not in patients. These findings provide preliminary evidence linking gray matter volumes in an extended network for error processing to the ERN, and suggest that structural alterations in this network may underlie exaggeration of the ERN in pediatric OCD.

Increased error-related brain activity in youth with obsessive-compulsive disorder and unaffected siblings.

BACKGROUND: The pathophysiology of obsessive-compulsive disorder (OCD) involves increased activity in cortico-striatal circuits connecting the anterior cingulate cortex (ACC) with other brain regions. The error-related negativity (ERN) is a negative deflection in the event-related potential following an erroneous response and is thought to reflect ACC activity. This study was done to assess the ERN as a biomarker for OCD by comparing ERN amplitudes in pediatric OCD patients, unaffected siblings of pediatric OCD patients, and healthy controls. METHODS: The ERN and correct response negativity (CRN) were measured during an Eriksen flanker task to assess performance monitoring in 40 youth with a lifetime diagnosis of OCD, 19 unaffected siblings of OCD patients, and 40 unrelated healthy comparison subjects ranging in age from 10 to 17 years. ERN and CRN amplitudes were compared between groups using linear regression by the generalized estimating equation method to account for correlated data. RESULTS: Compared to healthy controls, ERN amplitude was significantly increased in both pediatric OCD patients and unaffected siblings. There were no significant group differences in CRN amplitude. ERN amplitude in patients was unrelated to OCD symptom severity, current diagnostic status, or treatment effects. CONCLUSIONS: Increased error-related brain potentials were observed not only in pediatric OCD patients but also in unaffected siblings. The results provide evidence that enhanced error-related brain activity may serve as a biomarker for OCD in youth that is independent of the presence of clinical symptoms. The ERN may be a useful quantitative phenotype in genetic studies of OCD.

White matter volume and myelin oligodendrocyte glycoprotein (MOG) microsatellites in pediatric obsessive-compulsive disorder.

The myelin oligodendrocyte glycoprotein ( MOG ) gene plays an important role in myelination and has been implicated in the genetics of white matter changes in obsessive-compulsive disorder (OCD). We examined the association between variations of two microsatellite markers across MOG for association and total white matter volume as measured using volumetric MRI in 37 pediatric OCD patients 7-18 years. We compared white matter volumes between microsatellite allele groups using analysis of covariance with covariates of age, gender, and total intracranial volume. After controlling for multiple comparisons, a significant relationship was detected between MOG (TAAA)n and increased total white matter volume ( P  = 0.018-0.028). Although preliminary, our findings provide further support for the involvement of MOG in OCD.

Abnormally Enhanced Midfrontal Theta Activity During Response Monitoring in Youths With Obsessive-Compulsive Disorder.

BACKGROUND: Response monitoring, as reflected in electroencephalogram recordings after commission of errors, has been consistently shown to be abnormally enhanced in individuals with obsessive-compulsive disorder (OCD). This has traditionally been quantified as error-related negativity (ERN) and may reflect abnormal neurophysiological mechanisms underlying OCD. However, the ERN reflects the increase in phase-locked activities, particularly in the theta-band (4-8 Hz), and does not reflect non-phase-locked activities. To more broadly investigate midfrontal theta activity in a brain region that is essential for complex cognition, this study investigated theta abnormalities during response monitoring in participants with OCD to acheive a better understanding of the mechanism underlying the ERN. METHODS: Electroencephalogram data were recorded from 99 participants with pediatric OCD and 99 sex- and age-matched healthy control participants while they completed the arrow flanker task. Effects of group (OCD, healthy control) and response type (error, correct) on postresponse theta total power and intertrial phase coherence (ITPC) were examined using mixed analysis of covariance and Bayesian analyses controlling for sex and accuracy. RESULTS: Theta total power was larger on error than on correct trials and larger in OCD than healthy control participants, but there was no effect of response type between groups. Theta ITPC was larger on error than correct trials, but there was no group difference or response type difference between the groups. Correlations of theta total power and ITPC with clinical measures were overall small. CONCLUSIONS: Abnormally enhanced midfrontal theta total power, but not ITPC, may reflect ineffective heightened response monitoring or compensatory activity in pediatric OCD.

Error-related brain activity associated with obsessive-compulsive symptoms in youth.

BACKGROUND: Subclinical obsessive-compulsive symptoms (OCS) are common in children, and increase risk for later onset of obsessive-compulsive disorder (OCD). In pediatric patients with OCD, neuroimaging research implicates altered neural mechanisms for error-processing, but whether abnormal brain response occurs with subclinical OCS remains poorly understood. METHODS: Using functional magnetic resonance imaging (fMRI), 113 youth (8-18 years; 45 female) from a community sample were scanned during an error-eliciting Go/No-Go task. OCS were assessed dimensionally using the obsessive-compulsive subscale of the Child Behavior Checklist. The association between OCS scores and error-related brain activity was examined at the whole-brain level. RESULTS: Lower OCS scores associated with stronger response to errors in dorsal anterior cingulate cortex (dACC), caudate, putamen, thalamus, and occipital cortex. Additionally, lower OCS related to higher capacity for inhibitory control, as indexed by greater accuracy on No-Go trials during fMRI scanning. The relationship between lower OCS and better accuracy on No-Go trials was mediated by greater error-related dACC activity. CONCLUSIONS: The inverse relationship between OCS and error-related activity in the dACC and extended cortical-striatal-thalamic circuitry may index an adaptive process by which subclinical OCS are minimized in youth. Further, these results identify an observable pattern of brain activity that tracks with subclinical OCS severity. Understanding the link between neural networks for error processing and the normal to abnormal range of OCS may pave the way for brain-based strategies to identify children who are more likely to develop OCD and enable the targeting of preventive strategies to reduce risk.

Sustained attention induces altered effective connectivity of the ascending thalamo-cortical relay in obsessive-compulsive disorder.

Abnormal function of the thalamo-cortical relay is considered a hallmark of obsessive-compulsive disorder (OCD) and aberrant network interactions may underpin many of the clinical and cognitive symptoms that characterize the disorder. Several statistical approaches have been applied to in vivo fMRI data to support the general loss of thalamo-cortical connectivity in OCD. However, (a) few studies have assessed the contextual constraints under which abnormal network interactions arise or (b) have used methods of effective connectivity to understand abnormal network interactions. Effective connectivity is a particularly valuable method as it describes the putative causal influences that brain regions exert over each other, as opposed to the largely statistical consistencies captured in functional connectivity techniques. Here, using dynamic causal modeling (DCM), we evaluated how attention demand induced inter-group differences (HC ≠ OCD) in effective connectivity within a motivated thalamo-cortical network. Of interest was whether these effects were observed on the ascending thalamo-cortical relay, essential for the sensory innervation of the cortex. fMRI time series data from sixty-two participants (OCD, 30; HC, 32) collected using an established sustained attention task were submitted to a space of 162 competing models. Across the space, models distinguished between competing hypotheses of thalamo-cortical interactions. Bayesian model selection (BMS) identified marginally differing likely generative model architectures in OCD and HC groups. Bayesian model averaging (BMA), was used to weight connectivity parameter estimates across all models, with each parameter weighted by each model's posterior probability, thus providing more stable estimates of effective connectivity. Inferential statistical analyses of estimated parameters revealed two principal results: (1) Significantly reduced intrinsic connectivity of the V1 → SPC pathway in OCD, suggested connective weakness in the early constituents of the dorsal visual pathway; (2) More pertinent with the discovery possibilities afforded by DCM, sustained attention in OCD patients induced significantly reduced contextual modulation of the ascending relay from the thalamus to the prefrontal cortex. These results form an important complement to our understanding of the contextual bases of thalamo-cortical network deficits in OCD, emphasizing vulnerability of the ascending relay.

The OCI-CV-R: A Revision of the Obsessive-Compulsive Inventory - Child Version.

BACKGROUND: The Obsessive-Compulsive Inventory-Children's Version (OCI-CV) was developed to assess obsessive-compulsive symptoms in youth. Recent changes in the Diagnostic and Statistical Manual (DSM-5) exclude hoarding from inclusion in the diagnosis of obsessive-compulsive disorder (OCD). Accordingly, the present study examined the reliability, validity, factorial structure, and diagnostic sensitivity of a revised version of the scale - the OCI-CV-R- that excludes items assessing hoarding. METHODS: Participant were 1047 youth, including 489 meeting DSM criteria for primary OCD, 298 clinical controls, and 260 nonclinical controls, who completed the OCI-CV and measures of obsessive-compulsive symptom severity, depression, and anxiety at various treatment and research centers. RESULTS: Findings support a five-factor structure (doubting/checking, obsessing, washing, ordering, and neutralizing), with a higher order factor. Factorial invariance was found for older (12-17 years) and younger (7-11 years) children. Internal consistency of the OCI-CV-R was acceptable, and discriminant and convergent validity were adequate and akin to that of its progenitor. Diagnostic sensitivity and specificity were found for a total score of 8 and higher. CONCLUSION: It is recommended that the OCI-CV-R replace the former version, and that this measure serve as part of a comprehensive clinical assessment of youth with OCD. Recommendations for further research with ethnically and racially diverse samples, as well as the need to establish benchmark scores are discussed.

An ultra-brief screening scale for pediatric obsessive-compulsive disorder: The OCI-CV-5.

BACKGROUND: Obsessive-compulsive disorder (OCD) is an often disabling and chronic condition that is normally assessed using diagnostic interviews or lengthy self-report questionnaires. This makes routine screening in general health settings impractical, and as a result OCD is often under-(or mis-)recognized. The present study reports on the development of an ultra-brief version of the Obsessive-Compulsive Inventory-Child Version (OCI-CV) which may be administered routinely as a screener for pediatric OCD. METHOD: A total of 489 youth diagnosed with OCD, 259 non-clinical controls, and 299 youth with other disorders completed the OCI-CV and other indices of psychopathology. Using item analyses, we extracted five items and examined the measure's factor structure, sensitivity and specificity, and convergent and discriminant validity. RESULTS: We extracted five items that assess different dimensions of OCD (washing, checking, ordering, obsessing, neutralizing/counting), termed the OCI-CV-5. Results revealed that the measure possesses good to excellent psychometric properties, and a cutoff off (≥2) yielded optimal sensitivity and specificity. LIMITATIONS: Participants were predominantly White. In addition, more research is needed to examine the OCI-CV-5's test-retest reliability and sensitivity to treatment. CONCLUSIONS: The OCI-CV-5 shows promise as an ultra-brief self-report screener for identifying OCD in youth when in-depth assessment is unfeasible.

Associations of medication with subcortical morphology across the lifespan in OCD: Results from the international ENIGMA Consortium.

BACKGROUND: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. METHODS: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6-65) was divided into six successive 6-10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. RESULTS: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6-13 and adults aged 50-65 with OCD taking SRIs (Cohen's d = -0.24 to -0.74). Volumes of putamen, pallidum (d = 0.18-0.40), and ventricles (d = 0.31-0.66) were greater in patients aged 20-29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = -0.27 to -1.31). CONCLUSIONS: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20-29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

Major depressive disorder in a family study of obsessive-compulsive disorder with pediatric probands.

OBJECTIVE: This study examined the comorbidity of obsessive-compulsive disorder (OCD) with major depressive disorder (MDD) in a family study of OCD with pediatric probands. METHOD: This study assessed the lifetime prevalence of MDD in 141 first-degree relatives (FDR) and 452 second-degree relatives (SDR) of pediatric probands with OCD and healthy controls, and identified variables associated with MDD in case FDR. All available FDR were directly interviewed blind to proband status; parents were also interviewed to assess the family psychiatric history of FDR and SDR. Best-estimate diagnoses were made using all sources of information. Data were analyzed with logistic regression and robust Cox regression models. RESULTS: Lifetime MDD prevalence was significantly higher in case than in control FDR (30.4 versus 15.4%). Lifetime MDD prevalence was significantly higher in FDR of case probands with MDD than in FDR of case probands without MDD or control FDR (46.3 versus 19.7 versus 15.4%, respectively). MDD in case FDR was significantly associated with MDD in case probands and with age and OCD in those relatives. Lifetime MDD prevalence was similar in case and control SDR. However, lifetime MDD prevalence was significantly higher in SDR of case probands with MDD than in SDR of case probands without MDD or control SDR (31.9 versus 16.8 versus 15.4%, respectively). CONCLUSIONS: MDD prevalence was significantly higher in both FDR and SDR of case probands with MDD than in relatives of case probands without MDD or control relatives, suggesting that pediatric OCD comorbid with MDD is a complex familial syndrome.

An association of Myelin Oligodendrocyte Glycoprotein (MOG) gene variants with white matter volume in pediatric obsessive-compulsive disorder.

An increasing number of neuroimaging studies have implicated alterations of white matter in obsessive-compulsive disorder (OCD). The myelin oligodendrocyte glycoprotein (MOG) gene plays a major role in myelination, and has previously demonstrated significant association with this disorder, thus variations in this gene may contribute to observed white matter alterations. The purpose of this study is to examine the relationship between white matter volume in OCD and genetic variations in the MOG gene. Two polymorphisms in the MOG gene, MOG(C1334T) and MOG(C10991T), were investigated for association with total white matter volume as measured using volumetric magnetic resonance imaging in 37 pediatric OCD patients. We compared white matter volumes between allele and genotype groups for each polymorphism using ANCOVA. A significant relationship was detected between genotype C/C of MOG(C10991T) and decreased total white matter volume (P = 0.016). Our results showed an association between a MOG genetic variant and white matter volume. This finding is intriguing in light of the posited role of white matter alteration in the etiology of at least some cases of childhood-onset OCD. Further investigation with larger samples and sub-regional white matter volume phenotypes is warranted.

Evoking network profiles of the dorsal anterior cingulate in youth with Obsessive-Compulsive Disorder during motor control and working memory.

Interest in the pathology of Obsessive-Compulsive Disorder\has focused on brain network profiles of the dorsal Anterior Cingulate Cortex (dACC), given its role as a principal control region. Both motor control and working memory tasks induce dysfunctional dACC profiles in OCD. H H We contrasted dACC network profiles in OCD and age-comparable controls during both tasks (from data collected in the same participants). The motor task required participants to tap their right forefinger in response to a flashing white probe; the memory task was a standard n-back (2-Back) requiring participants to identify if a current stimulus was identical to the one presented two items before it in the sequence. Network interactions were modeled using Psychophysiological Interactions (PPI), a model of directional functional connectivity. Inter-group analyses indicated a) that the motor control task evoked greater dACC modulation than the working memory task, and b) that the modulatory effect was significantly greater in the OCD group. We also investigated the relationship between OCD symptom dimensions (lifetime obsession and lifetime compulsion measured using the CY-BOCS) and dACC network profiles in OCD. This analysis revealed a dichotomy between Obsessive-Compulsive symptom dimensions and the degree of dACC modulation: primarily increased obsessions predicted increased modulation during the motor control task, but primarily increased compulsions predicted increased modulation during the working memory task. These results re-emphasize the salience of the dACC in OCD, and the primacy of tasks of motor control in evoking dACC pathology in the disorder.

Clinical validation of the parent-report Toronto Obsessive-Compulsive Scale (TOCS): A pediatric open-source rating scale.

Background: There is a need to develop a multipurpose obsessive-compulsive disorder (OCD) measure that is useful for cross disorder research and as a reliable clinical rating scale. The current study examined the psychometric properties and established clinical cutoffs for the parent-report version of the Toronto Obsessive-Compulsive Scale (TOCS), a 21-item rating scale of obsessive-compulsive traits. Method: Participants ranged in age from 6 to 21 years old and had a primary diagnosis of OCD (n = 350, 50% female), attention-deficit/hyperactivity disorder (ADHD) (n = 820, 25% female), autism spectrum disorder (ASD) (n = 794, 22% female), or were typically developing controls (n = 391, 51% female). Confirmatory factor analyses, internal consistency reliability, and convergent and divergent validity of the TOCS were examined in the OCD group. Using various scoring approaches, receiver operating characteristic (ROC) analyses were used to establish a clinical cut-off by splitting the OCD group into a discovery sample (166 OCD cases, 164 controls) and a validation sample (184 OCD cases, 227 controls). Classification accuracy and TOCS scores were compared across OCD, ADHD, and ASD groups. Results: The psychometric properties of the TOCS were confirmed. ROC analyses across TOCS scoring approaches in the discovery sample indicated excellent diagnostic discrimination (AUC ≥0.95, sensitivity 77%-92%, specificity 92%-98%). Established cutoffs, when applied in the independent validation sample of OCD cases and controls, showed an overall classification accuracy of 85%-90%. The TOCS total score and symptom count showed good discrimination of OCD from ADHD (AUC ≥0.86) and ASD (AUC ≥0.81). The OCD group scored significantly higher on all TOCS dimensions (except Hoarding) than the ADHD and ASD groups. Conclusion: The TOCS is a reliable and valid rating scale with strong sensitivity and specificity in discriminating OCD cases from controls, as well as from ASD and ADHD. It is a quantitative OCD measure with important clinical and research applications, with particular relevance for cross disorder phenotyping and population-based studies.

Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder.

Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10-8). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p's < 0.01). OC traits were highly, but not significantly, genetically correlated with OCD (rg = 0.71, p = 0.062). We report the first validated genome-wide significant variant for OC traits in PTPRD, downstream of the most significant locus in a previous OCD GWAS. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the feasibility and power of using trait-based approaches in community samples for genetic discovery.