The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum

Mahjani, Behrang; Klei, Lambertus; Mattheisen, Manuel; Halvorsen, Matthew; Reichenberg, Abraham; Roeder, Kathryn; Pedersen, Nancy L.; Boberg, Julia; Schipper, Elles de; Bulik, Cynthia M.; Landén, Mikael; Fundin, Bengt T.; Mataix‐Cols, David; Sandin, Sven; Hultman, Christina M.; Crowley, James J.; Buxbaum, Joseph D.; Rück, Christian; Devlin, Bernie; Grice, Dorothy E.

doi:10.1176/appi.ajp.2021.21010101

Cited by 21 publications

(8 citation statements)

References 46 publications

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“…With an estimated 4.1% the SNP-based heritability also stands in stark contrast with heritability estimates observed in twin studies (37-41%; (64)). However, in line with previous research reports, we found a lower SNP-based heritability for OCS (12,13) than for clinical OCD (0.28-0.37) (65,66). The reason for the disparity in SNP heritability between traits and diagnosis is unclear but could be explained by the fact that clinical diagnosed OCD represents the extreme of the OCS distribution in the general population.…”

Section: Discussionsupporting

confidence: 89%

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

Strom

Burton

Iyegbe

et al. 2022

Preprint

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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 x10-5). 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.

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Section: Discussionsupporting

confidence: 89%

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

Strom

Burton

Iyegbe

et al. 2022

Preprint

Self Cite

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“…It has been suggested that the onset and exacerbation of OCD symptoms are dependent on genetic factors [11,12], with reports on heritability point estimates reaching 0.37 [13]. A recent study based on Swedish-born individuals con rmed that common genetic risk variants account for most of the heritable variation in OCD and suggested polygenic architecture of this complex disorder [14]. Additionally, a population-based study suggested that the increased familial risk of OCD was attributable to additive genetic factors (47%), but that non-shared environmental factors were estimated to be as important as the genetic contributions [15].…”

Section: Introductionmentioning

confidence: 99%

Clinical description and epigenetic profiling of a new Danish OCD case-control cohort

Staunstrup,

Starnawska,

Bybjerg-Grauholm

et al. 2023

Preprint

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Background Obsessive compulsive disorder (OCD) is a frequent and severe neuropsychiatric disorder, with cardinal features being obsessions and compulsions. The complex nature of OCD has complicated efforts to identify its causal mechanisms, however, genetic and epigenetic factors have been proposed to contribute to the pathophysiology of the disorder. The aim of the study was to provide a clinical description of a novel OCD case-control cohort created to study epigenetic risk factors and lifetime epigenetic trajectories associated with OCD. Methods The cohort consisted of 138 OCD cases and 151 control ethnical Danish individuals. Mental health status for all study participants was evaluated according to selected parts of the K-SADS-PL diagnostic instrument. Additionally, baseline OCD symptoms, Children’s Yale Brown Obsessive Compulsive Scale (CYBOCS) scores, insight, avoidance behavior, doubt, responsibility, sensitivity, social aspects, school functioning, medication, and family occurrence of psychiatric and somatic disorders information was collected for OCD cases. Blood genome-wide DNA methylation (DNAm) levels were quantified with Illumina’s EPIC methylation array at birth and at adolescents for all study participants. Results This work provides a clinical description of the cohort, and the first results from OCD epigenome-wide association studies performed at two developmental stages: neonatal and adolescent. We have identified several DMRs to be associated with OCD diagnosis (Šidák-adjusted DMR p-value < 0.05), both at birth and adolescence, including three DMRs overlapping across the two developmental stages. The DNAm change in the overlapping DMRs was observed to be in the same direction and two of the findings (ZFP57, PIWIL1) had previously been associated with OCD and treatment response. Furthermore, the third DMR associated with OCD at both stages was annotated to POU6F2, a gene previously suggested to be involved in schizophrenia and autism development. Conclusions Overall, our data suggests that differences in DNAm levels in genes implicated in mental illness are associated with OCD diagnosis, and that some of these epigenetic signals can be detected both at birth and at adolescence. Future studies using the same cohort will aim at investigating longitudinal changes in epigenomic trajectories associated with the disorder and its treatment outcomes.

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“…To date, most genetic studies of OCD have primarily focused on the impact of common heritable variation on risk. However, there is increasing evidence implicating the role of rare variants in risk for OCD [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Phenotypic Impact of Rare Potentially Damaging Copy Number Variation in Obsessive-Compulsive Disorder and Chronic Tic Disorders

Mahjani

Birnbaum

Grice

et al. 2022

Genes

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Background: Recent studies report an important—and previously underestimated—role of rare variation in risk of obsessive-compulsive disorder (OCD) and chronic tic disorders (CTD). Using data from a large epidemiological study, we evaluate the distribution of potentially damaging copy number variation (pdCNV) in OCD and CTD, examining associations between pdCNV and the phenotypes of probands, including a consideration of early- vs. late-diagnoses. Method: The Obsessive-Compulsive Inventory-Revised (OCI-R) questionnaire was used to ascertain psychometric profiles of OCD probands. CNV were identified genome-wide using chromosomal microarray data. Results: For 993 OCD cases, 86 (9%) were identified as pdCNV carriers. The most frequent pdCNV found was at the 16p13.11 region. There was no significant association between pdCNV and the OCI-R total score. However, pdCNV was associated with Obsessing and Checking subscores. There was no significant difference in pdCNV frequency between early- vs. late-diagnosed OCD probands. Of the 217 CTD cases, 18 (8%) were identified as pdCNV carriers. CTD probands with pdCNV were significantly more likely to have co-occurring autism spectrum disorder (ASD). Conclusions: pdCNV represents part of the risk architecture for OCD and CTD. If replicated, our findings suggest pdCNV impact some OCD symptoms. Genes within the 16p13.11 region are potential OCD risk genes.

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The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum

Cited by 21 publications

References 46 publications

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

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

Clinical description and epigenetic profiling of a new Danish OCD case-control cohort

Phenotypic Impact of Rare Potentially Damaging Copy Number Variation in Obsessive-Compulsive Disorder and Chronic Tic Disorders

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