Summary: A new study links rare de novo genetic changes—copy number variants (CNVs)—to pediatric obsessive-compulsive disorder (OCD). Using whole-exome sequencing (WES) on nearly 1,000 family trios, researchers detected a markedly higher rate of these spontaneous genetic events in children with OCD compared with unaffected peers. These findings highlight a noninherited genetic contribution to OCD risk and point to neurodevelopmental processes that may underlie the disorder.
The research does not provide a cure, but it builds an important biological foundation for earlier diagnosis, improved precision in treatment, and a clearer understanding of the genetic architecture of pediatric OCD.
Key Facts:
- Large enrichment of rare CNVs: Children with OCD had about 14 times more rare de novo CNVs than healthy controls in this sample.
- Neurodevelopmental impact: Approximately 75% of the identified de novo CNVs in patients were predicted to be pathogenic or likely pathogenic and implicated genes involved in brain development.
- Clinical and research potential: The study’s CNV calls are now available to support integrated genetic analyses and may help guide future precision diagnosis and therapeutic research.
Source: FAPESP
Overview
Researchers report the first demonstration, using whole-exome sequencing, that rare de novo copy number variants are enriched in pediatric OCD. The study strengthens prior evidence that genetics play an important role in obsessive-compulsive disorder and extends those insights by identifying spontaneous structural changes in DNA that are likely to affect neurodevelopmental pathways.
In their analysis, the investigators found that 7 out of 100 children with OCD carried a rare de novo CNV, compared with 0.5 out of 100 in healthy children. Pediatric OCD is a common neuropsychiatric disorder influenced by genetic and environmental factors; it affects a significant portion of the population and is characterized by distressing obsessions and/or compulsions that interfere with daily functioning. Current treatment strategies focus on symptom management and quality-of-life improvement.
To detect CNVs, the team applied whole-exome sequencing (WES) to data from 183 OCD trios (affected child and both unaffected parents) and 771 control trios. Samples came from multiple centers in São Paulo (Brazil), New Haven (United States), Toronto and Ontario (Canada). CNVs are structural variations in DNA where segments are duplicated or deleted; when they arise for the first time in a child and are absent from both parents, they are classified as de novo. Such de novo events can be benign or, depending on their genomic location and size, can disrupt genes and biological processes relevant to disease.
“Everyone has de novo mutations; that’s evolution. The critical question is where those variants occur in the genome, which biological processes they affect, and whether they are deleterious,” said Carolina Cappi, a coauthor and researcher at the Department of Psychiatry at the Icahn School of Medicine at Mount Sinai. Cappi, who also collaborates with the Center for Research and Innovation in Mental Health (CISM) in Brazil, noted that separating de novo variants from inherited rare variants revealed the significant association with OCD—particularly deletions.
The study was supported by FAPESP through two projects (21/12901-9 and 14/50917-0) and was conducted in collaboration with investigators including Euripedes Constantino Miguel Filho, a psychiatrist and professor at the University of São Paulo Medical School.
Findings and interpretation
Published in the Journal of the American Academy of Child & Adolescent Psychiatry, the study reports that the majority of rare de novo CNVs identified in children with OCD were predicted to be pathogenic or likely pathogenic; none of these potentially damaging CNVs were found in the control sample. Gene-set analyses showed enrichment in biological pathways relevant to brain development, suggesting that the CNVs detected are nonrandom and likely contribute to OCD risk.
Thomas Fernandez, a child psychiatrist at Yale School of Medicine and the paper’s corresponding author, described the findings as an important advance in understanding the genetic roots of OCD. He emphasized that this research is a foundational step that complements other genetic studies and can inform future efforts aimed at targeted therapies and precise diagnosis.
The study’s CNV dataset has been made available to other research groups to support broader, integrated analyses aimed at clarifying genetic risk factors across diverse samples.
Collaborative network and sample diversity
The project builds on long-term collaborative efforts. In 2008, the Brazilian Consortium for Research on Obsessive-Compulsive Spectrum Disorders (CTOC) began collecting clinical data across seven centers in Brazil. More recently, the Brazil Genetic/Phenotype OCD Working Group (GTTOC) was formed, involving ten centers and incorporating genomic data into phenotypic studies. The group collects biological samples across seven states, collaborates with international projects, and conducts outreach to increase sample diversity and reduce stigma. Their current sample includes nearly 300 affected families and about 1,200 individuals with OCD, enabling studies that reflect varied social and ethnic backgrounds.
About this genetics and OCD research news
Author: Joao Silva
Source: FAPESP
Contact: Joao Silva – FAPESP
Image: Image credited to Neuroscience News
Original Research: Open access. “Characterizing Rare DNA Copy-Number Variants in Pediatric Obsessive-Compulsive Disorder” by Carolina Cappi et al. Journal of the American Academy of Child & Adolescent Psychiatry. DOI: 10.1016/j.jaac.2025.03.014
Abstract
Characterizing Rare DNA Copy-Number Variants in Pediatric Obsessive-Compulsive Disorder
Objective
Pediatric OCD is a common neuropsychiatric disorder with an important genetic component. Prior work has shown enrichment of rare de novo single-nucleotide variants in OCD and has examined CNVs using microarray data. This study uses whole-exome sequencing to identify rare de novo CNVs and to explore genetic factors and biological pathways that may contribute to OCD risk.
Method
CNVs were detected in WES data from 183 OCD trios and 771 control trios. The primary CNV-calling approach used the eXome-Hidden Markov Model (XHMM) to identify CNVs in silico, followed by burden analyses and downstream biological systems analyses. A second algorithm (GATK-gCNV) was used to confirm the primary results.
Results
The study found a higher rate of rare de novo CNVs in persons with OCD (0.07 CNVs per proband) versus controls (0.005), yielding a corrected rate ratio of 11.7 (95% CI = 3.6–50.0, p = 4.00×10^-6). Confirmation with GATK-gCNV supported this enrichment. Most rare de novo CNVs in OCD probands were predicted to be pathogenic or likely pathogenic, and affected genes showed enrichment in relevant Gene Ontology sets.
Conclusion
This study demonstrates for the first time an enrichment of rare de novo CNVs detected by whole-exome sequencing in pediatric OCD, complementing previous CNV research and advancing understanding of genetic factors that contribute to OCD risk.