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Characterizing rare DNA copy-number variants in pediatric obsessive-compulsive disorder

O artigo Characterizing rare DNA copy-number variants in pediatric obsessive-compulsive disorder publicado no Journal of the American Academy of Child & Adolescent Psychiatry

New research

Characterizing Rare DNA Copy-Number Variants in Pediatric Obsessive-Compulsive Disorder

Elements of this study were presented at the American Academy of Child and Adolescent Psychiatry’s 66th Annual Meeting; October 14-19, 2019; Chicago, Illinois, and the Society of Biological Psychiatry’s 77th Annual Meeting; April 28-30, 2022; New Orleans, Louisiana.
https://doi.org/10.1016/j.jaac.2025.03.014Get rights and content
Referred to by
Editorial: Exploring Rare Genetic Variation in Pediatric-Onset Obsessive-Compulsive Disorder: Some Excitement and Some Uncertainty
Journal of the American Academy of Child & Adolescent Psychiatry, Available online 18 June 2025, Pages
Dorothy E. Grice

Objective

Pediatric obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder in which genetic factors play an important role. Recent studies have demonstrated an enrichment of rare de novo DNA single-nucleotide variants in persons with OCD compared to controls, and larger studies have examined copy-number variants (CNVs) using microarray data. Our study examines rare de novo CNVs using whole-exome sequencing (WES) data to provide additional insight into genetic factors and biological processes underlying OCD.

Method

We detected CNVs using whole-exome DNA sequencing (WES) data from 183 OCD trio families (unaffected parents and children with OCD) and 771 control families to test the hypothesis that rare de novo CNVs are enriched in persons with OCD compared to controls. Our primary analysis used the eXome-Hidden Markov Model (XHMM) to identify CNVs in silico. We performed burden analyses comparing persons with OCD vs controls and downstream biological systems analyses of CNVs in probands with OCD. We then used a second algorithm (GATK-gCNV) to confirm our primary analysis.

Results

Our findings demonstrate a higher rate of rare de novo CNVs detected by WES in persons with OCD (0.07 CNVs per proband) compared to controls (0.005) (corrected rate ratio = 11.7 95% CI = 3.6-50.0, p = 4.00×10-6). We confirmed this enrichment using GATK-gCNV. The majority of these rare de novo CNVs in persons with OCD are predicted to be pathogenic or likely pathogenic, and an examination of genes disrupted by rare de novo CNVs in persons with OCD finds enrichment of several Gene Ontology sets.

Conclusion

This study shows for the first time an enrichment of rare de novo CNVs detected by WES in OCD, complementing previous, larger CNV studies and providing additional insight into genetic factors underlying OCD risk.

Section snippets

Data Collection and Processing

Participant recruitment, sample collection, and whole-exome DNA sequencing (WES) were performed as described in our previous report.14 In brief, we generated WES data from peripheral blood DNA of 686 individuals from parent–child OCD trios recruited in Toronto, Ontario, Canada; São Paulo, Brazil; and New Haven, Connecticut; and from a separate Tourette International Collaborative Genetics (TIC Genetics) study that included patients with both OCD and chronic tics.33,34 To enrich for de novo

CNV Mutation Rates and Burden Analysis

For our primary analysis (XHMM, minimum 6-exome target) in our sample of OCD probands, although our sample size resulted in wide confidence intervals, we detected a rare de novo CNV rate of 0.07 per individual (95% CI = 0.04-0.12). We observed a significant enrichment of rare de novo CNVs in OCD probands compared to controls (0.07 vs 0.005 per individual, 95% CI = 0.001-0.01), corrected rate ratio = 11.7, 95% CI = 3.56-50.0, p = 4.00×10-6). This difference appears to be driven by a

Discussion

This study demonstrates for the first time an enrichment of rare de novo CNVs detected by whole-exome sequencing in individuals with OCD compared to controls, complementing previous larger-scale CNV studies using microarray data. Our findings suggest that this type of genetic variation contributes to OCD pathogenesis, and provide additional insight into genetic factors underlying OCD. Specifically, we observed that the proportion of individuals with and the per individual rate of de novo CNVs

CRediT authorship contribution statement

Sarah B. Abdallah: Writing – review & editing, Writing – original draft, Visualization, Validation, Software, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Emily Olfson: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Carolina Cappi: Writing – review & editing, Resources, Investigation,

 

Fonte: https://www.sciencedirect.com/science/article/abs/pii/S0890856725001601