Genome-Wide Association Study in Obsessive-Compulsive Disorder: Results from the OCGAS

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients, with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1 065 families (containing 1 406 patients with OCD), combined with population-based samples (resulting in a total sample of 5 061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at SNP- and gene-levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13×10−7). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of GWAS signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2, and PTPRD. Analyses at the gene-level revealed association of IQCK and C16orf88 (both P<1×10−6, experiment-wide significant), as well as OFCC1 (P=6.29×10−5). The suggestive findings in this study await replication in larger samples

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Principal components analysis of obsessive-compulsive disorder symptoms in children and adolescents

; Background: Obsessive-compulsive disorder (OCD) has a broadly diverse clinical expression that may reflect etiologic heterogeneity. Several adult studies have identified consistent symptom dimensions of OCD. the purpose of this, study was to conduct an exploratory principal components analysis of obsessive-compulsive (OC)symptoms in children and adolescents with OCD to identify improved phenotypes for future studies.Methods: This study examined 1 lifetime occurrence of OC symptoms included in the 13 symptom categories of the Yale Brown Obsessive Compulsive Scale (Y-BOCS) and the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Principal components analysis with promax rotation was performed on 231 children and adolescents with OCD and compared with results of similar adult studies.Results. A four-factor solution emerged explaining 59.8% of symptom variance characterized by 1) symmetry/ordering-repeating/checking ; 2) contamination/cleaning/aggressive; 3) boarding; and 4) sexual/religious symptoms. All factors included core symptoms that have been consistently observed in adult studies of OCD.Conclusions: in children and adolescents, OCD is a multidimensional disorder. Symptom dimensions are predominantly congruent with those described in similar studies of adults with OCD, suggesting fair y consistent covariation of OCD symptoms through the developmental course. Future work is required to understand changes in specific symptom dimensions observed across the life span.Harvard Univ, Massachusetts Gen Hosp, Sch Med, Psychiat & Neurodev Genet Unit,Dept Psychiat, Boston, MA 02114 USAUniversidade Federal de São Paulo, Dept Psychiat, São Paulo, BrazilUniv Massachusetts, Dept Psychol, Boston, MA 02125 USABoston Univ, Dept Psychol, Boston, MA 02215 USAYale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USAUniversidade Federal de São Paulo, Dept Psychiat, São Paulo, BrazilWeb of Scienc

Neurocognitive function in paediatric obsessive-compulsive disorder

<p><b>Objectives:</b> The small body of neuropsychological research in paediatric obsessive-compulsive disorder (OCD) yields inconsistent results. A recent meta-analysis found small effect sizes, concluding that paediatric OCD may not be associated with cognitive impairments, stressing the need for more research. We investigated neuropsychological performance in a large sample of youths with OCD, while assessing potential moderators.</p> <p><b>Methods:</b> Participants with OCD (<i>n</i> = 102) and matched controls (<i>n</i> = 161) were thoroughly screened and blindly evaluated for comorbidities, and completed a neuropsychological battery assessing processing speed, visuospatial abilities (VSA), working memory (WM), non-verbal memory (NVM), and executive functions (EF).</p> <p><b>Results:</b> Compared to controls, youths with OCD exhibited underperformance on tasks assessing processing speed. On tests of VSA and WM, underperformance was found only on timed tasks. There were no differences on NVM and EF tasks. Notably, the OCD group’s standardised scores were in the normative range. Test performance was not associated with demographic or clinical variables.</p> <p><b>Conclusions:</b> Youths with OCD exhibited intact performance on memory and EF tests, but slower processing speed, and underperformance only on timed VSA and WM tasks. While the OCD group performed in the normative range, these findings reveal relative weaknesses that may be overlooked. Such an oversight may be of particular importance in clinical and school settings.</p

Te Ara Waiora-Implementing human papillomavirus (HPV) primary testing to prevent cervical cancer in Aotearoa New Zealand: A protocol for a non-inferiority trial.

BackgroundCervical cancer is caused by high-risk types of human papillomavirus (HPV). Testing for high-risk HPV is a more sensitive screening method than cervical cytology for detecting cervical changes that may lead to cancer. Consistent with recent evidence of efficacy and acceptability, Aotearoa New Zealand plans to introduce HPV testing as the primary approach to screening, replacing cervical cytology, from mid-2023. Any equitable cervical screening programme must be effective across a diverse population, including women that the current programme fails to reach, particularly Māori and those in rural areas. Currently, we do not know the best model for implementing an equitable HPV self-testing screening programme.MethodsThis implementation trial aims to assess whether a universal offer of HPV self-testing (offered to all people eligible for cervical screening) achieves non-inferior screening coverage (equal) to a universal offer of cervical cytology alone (the present programme). The study population is all people aged from 24.5 to 70 years due for cervical screening in a 12-month period (including those whose screening is overdue or who have never had screening). A range of quantitative and qualitative secondary outcomes will be explored, including barriers and facilitators across screening and diagnostic pathways. This study takes place in Te Tai Tokerau/Northland which covers a diverse range of urban and rural areas and has a large Indigenous Māori population. A total of fourteen practices will be involved. Seven practices will offer HPV self-testing universally to approximately 2800 women and will be compared to seven practices providing routine clinical care (offer of cervical cytology) to an approximately equal number of women.DiscussionThis trial will answer important questions about how to implement an equitable, high-quality, effective national programme offering HPV self-testing as the primary screening method for cervical cancer prevention.Trial registrationProspectively registered with the Australian New Zealand Clinical Trials Registry 07/12/2021: ACTRN12621001675819

Te Ara Waiora–Implementing human papillomavirus (HPV) primary testing to prevent cervical cancer in Aotearoa New Zealand: A protocol for a non-inferiority trial

Background Cervical cancer is caused by high-risk types of human papillomavirus (HPV). Testing for high-risk HPV is a more sensitive screening method than cervical cytology for detecting cervical changes that may lead to cancer. Consistent with recent evidence of efficacy and acceptability, Aotearoa New Zealand plans to introduce HPV testing as the primary approach to screening, replacing cervical cytology, from mid-2023. Any equitable cervical screening programme must be effective across a diverse population, including women that the current programme fails to reach, particularly Māori and those in rural areas. Currently, we do not know the best model for implementing an equitable HPV self-testing screening programme. Methods This implementation trial aims to assess whether a universal offer of HPV self-testing (offered to all people eligible for cervical screening) achieves non-inferior screening coverage (equal) to a universal offer of cervical cytology alone (the present programme). The study population is all people aged from 24.5 to 70 years due for cervical screening in a 12-month period (including those whose screening is overdue or who have never had screening). A range of quantitative and qualitative secondary outcomes will be explored, including barriers and facilitators across screening and diagnostic pathways. This study takes place in Te Tai Tokerau/Northland which covers a diverse range of urban and rural areas and has a large Indigenous Māori population. A total of fourteen practices will be involved. Seven practices will offer HPV self-testing universally to approximately 2800 women and will be compared to seven practices providing routine clinical care (offer of cervical cytology) to an approximately equal number of women. Discussion This trial will answer important questions about how to implement an equitable, high-quality, effective national programme offering HPV self-testing as the primary screening method for cervical cancer prevention. Trial registration Prospectively registered with the Australian New Zealand Clinical Trials Registry 07/12/2021: ACTRN12621001675819

Immune-Related Comorbidities in Childhood-Onset Obsessive Compulsive Disorder: Lifetime Prevalence in the Obsessive Compulsive Disorder Collaborative Genetics Association Study.

Objective: To evaluate the lifetime prevalence of infectious, inflammatory, and autoimmune disorders in a multisite study of probands with childhood-onset obsessive compulsive disorder (OCD) and their first-degree relatives. Methods: Medical questionnaires were completed by 1401 probands and 1045 first-degree relatives in the OCD Collaborative Genetics Association Study. Lifetime prevalence of immune-related diseases was compared with the highest available population estimate and reported as a point estimate with 95% adjusted Wald interval. Worst-episode OCD severity and symptom dimensions were assessed with the Yale-Brown Obsessive Compulsive Scale (YBOCS) and Symptom Checklist (YBOCS-CL). Results: Probands reported higher-than-expected prevalence of scarlet fever (4.0 [3.1-5.2]% vs. 1.0%-2.0%, z = 1.491, p &lt; 0.001, n = 1389), encephalitis or meningitis (1.4 [0.9-2.1]% vs. 0.1%-0.4%, z = 5.913, p &lt; 0.001, n = 1393), rheumatoid arthritis (1.1 [0.6-2.0]% vs. 0.2%-0.4%, z = 3.416, p &lt; 0.001, n = 949) and rheumatic fever (0.6 [0.3-1.2]% vs. 0.1%-0.2%, z = 3.338, p &lt; 0.001, n = 1390), but not systemic lupus erythematosus, diabetes, asthma, multiple sclerosis, psoriasis, or inflammatory bowel disease. First-degree relatives reported similarly elevated rates of scarlet fever, rheumatic fever, and encephalitis or meningitis independent of OCD status. There was no association between worst-episode severity and immune-related comorbidities, although probands reporting frequent ear or throat infections had increased severity of cleaning-/contamination-related symptoms (mean factor score 2.5 ± 0.9 vs. 2.3 ± 1.0, t = 3.183, p = 0.002, n = 822). Conclusion: These data suggest high rates of streptococcal-related and other immune-mediated diseases in patients with childhood-onset OCD and are consistent with epidemiological studies in adults noting familial clustering. Limitations include potential reporting bias and absence of a control group, underscoring the need for further prospective studies characterizing medical and psychiatric disease clusters and their interactions in children. Such studies may ultimately improve our understanding of OCD pathogenesis and aid in the development of adjunctive immune-modulating therapeutic strategies