Summary: In a groundbreaking study, researchers have linked rare “de novo” genetic mutations—copy number variants (CNVs)—to pediatric obsessive-compulsive disorder (OCD). Using whole exome sequencing on nearly 1,000 families, they found significantly more of these mutations in children with OCD than in healthy peers.
The findings help explain why OCD may arise even without inherited genetic risk and suggest the disorder has deeper roots in spontaneous genetic changes. While not a cure, the discovery lays a foundation for earlier diagnosis, better treatments, and a clearer understanding of OCD’s biological underpinnings.
Key Facts:
- Rare CNVs Identified: Children with OCD had 14 times more rare de novo CNVs than healthy children.
- Neurodevelopmental Link: 75% of these mutations were potentially harmful and linked to brain development.
- Future Potential: The study provides a genetic blueprint that could inform precision diagnosis and therapies.
Source: FAPESP
Researchers have demonstrated a specific type of genetic variation in obsessive-compulsive disorder (OCD) for the first time using advanced DNA sequencing technology.
The findings support previous studies by the same group and help build a more complete picture of how genetics contributes to and influences the development of the disorder. They also pave the way for future research into earlier diagnosis and targeted treatments.
The study concluded that children with OCD have significantly higher rates of rare copy number variants (CNVs) in their DNA than healthy children – seven out of every 100 patients, versus only 0.5 out of every 100 healthy children. Pediatric OCD is a common psychiatric disorder in which genetic factors play an important role.
There is still no cure for the problem, which affects between 1% and 3% of the global population, according to estimates by the World Health Organization (WHO). It is characterized by obsessions (unwanted thoughts) and/or compulsions (repetitive behaviors) that cause significant distress and interfere with social and professional relationships.
Current treatments aim to manage symptoms and improve quality of life.
For the study, the scientists used a cutting-edge DNA analysis technique called whole exome sequencing (WES). They analyzed data from 183 families of trios with OCD and 771 without the disorder (controls) from São Paulo (Brazil), New Haven (United States), and Toronto and Ontario (Canada).
CNVs refer to circumstances in which the number of copies of a specific DNA segment varies among different individuals. These variations can be short or include thousands of bases, or kilobases, a measure of DNA size.
These differences can arise through duplications, when a piece of DNA appears repeated, or deletions, when a piece is missing. In some cases, CNVs are inherited, but if they appear for the first time in a person and are not present in their parents, they are called “de novo.” Depending on the region of DNA affected, CNVs may be related to diseases.
“Everyone has ‘de novo’ mutations; that’s evolution. The question is the location of these variants in the genome, what processes they’re influencing, and whether they’re deleterious, for example.
“When we analyze rare variants – inherited and ‘de novo’ – there’s no significant difference between families with OCD and control families. When we separate the ‘de novo’ variants, the differences are significant, with deletion ‘pulling’ the association with the disorder.
“We’ve shattered a paradigm on the issue of inheritance from parents,” explains Carolina Cappi, one of the authors of the article and a researcher at the Department of Psychiatry of the Icahn School of Medicine at Mount Sinai Hospital in New York.
Cappi is also a collaborator at the Center for Research and Innovation in Mental Health (CISM) in Brazil. CISM is a partnership between the University of São Paulo (USP) and the federal universities of São Paulo (UNIFESP) and Rio Grande do Sul (UFRGS). FAPESP supported the work through two projects (21/12901-9 and 14/50917-0).
Both projects are led by Euripedes Constantino Miguel Filho, a psychiatrist and professor at the USP Medical School and one of the authors of the article.
Results
The research, published in the Journal of the American Academy of Child & Adolescent Psychiatry, found that 75% of genetic variants identified in patients with OCD were considered potentially harmful, whereas none were identified in healthy controls.
The results suggest that these genetic differences are not random – they likely contribute to the risk of developing the disorder.
“This research represents an important step forward in understanding the genetic roots of OCD, although it should be viewed as part of a larger puzzle. This is fundamental science that may bear fruit by providing an important foundation for future research that could eventually lead to better treatments.
“It’s a significant step in a long journey toward fully understanding this complex disorder,” Thomas Fernandez, a child psychiatrist specializing in OCD at Yale School of Medicine and corresponding author of the article, told Agência FAPESP.
The CNV detections from the study are now available to assist other groups with future integrated analyses.
Long-standing partnership
In 2008, Miguel Filho and his colleagues established the Brazilian Consortium for Research on Obsessive-Compulsive Spectrum Disorders (CTOC). Seven centers across Brazil collected clinical data from individuals with OCD to study characteristics of the disorder.
Almost 15 years later, Cappi created the Brazil Genetic/Phenotype OCD Working Group (GTTOC) with the collaboration of ten Brazilian centers, and genomic data began to be incorporated and analyzed. Composed of psychiatrists, psychologists, nurses, and biologists, this group provides clinical and research training to centers in different regions of Brazil, many of which do not specialize in treating OCD.
In addition to collecting clinical data, the GTTOC collects biological material in seven states and collaborates with two international projects. The group created an Instagram channel (@somosgentoc) to increase sample diversity, reduce the stigma associated with psychiatric disorders, and share science in an accessible way.
The channel brings findings from scientific articles and concepts about genetics, mental health, and forms of treatment for OCD to the public. This allows the group to reach people who often lack access to hospitals or live in remote areas of the country.
The diversity of the sample allows for broader studies of different social determinants and ethnic groups. Currently, the group’s sample includes nearly 300 families of patients with OCD, as well as 1,200 individuals with the disorder.
About this genetics and OCD research news
Author: Joao Silva
Source: FAPESP
Contact: Joao Silva – FAPESP
Image: The image is 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
Abstract
Characterizing Rare DNA Copy-Number Variants in Pediatric Obsessive-Compulsive Disorder
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.
