Journal of the American Academy of Child and Adolescent Psychiatry · 2025
Characterizing Rare DNA Copy-Number Variants in Pediatric Obsessive-Compulsive Disorder.
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Abdallah Sarah B, Olfson Emily, Cappi Carolina, Greenspun Samantha, Zai Gwyneth, Rosário Maria C, Willsey A Jeremy, Shavitt Roseli G, Miguel Euripedes C, Kennedy James L, Richter Margaret A, Fernandez Thomas V
Аннотация
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.
PLAIN LANGUAGE SUMMARY: Using DNA sequencing data from 183 children with obsessive-compulsive disorder (OCD) and their parents, alongside 771 families without OCD, researchers identified rare spontaneous changes in DNA where large segments are duplicated or deleted copy-number variants [CNVs]. This study found that these spontaneous (de novo) DNA changes occurred more frequently in children with OCD compared to children without OCD (7% vs 0.5% of children). These findings demonstrate that spontaneous genetic changes may contribute to OCD risk and highlight specific genes that may be important for understanding how OCD develops, providing new avenues for future research into this common psychiatric condition.
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.
PLAIN LANGUAGE SUMMARY: Using DNA sequencing data from 183 children with obsessive-compulsive disorder (OCD) and their parents, alongside 771 families without OCD, researchers identified rare spontaneous changes in DNA where large segments are duplicated or deleted copy-number variants [CNVs]. This study found that these spontaneous (de novo) DNA changes occurred more frequently in children with OCD compared to children without OCD (7% vs 0.5% of children). These findings demonstrate that spontaneous genetic changes may contribute to OCD risk and highlight specific genes that may be important for understanding how OCD develops, providing new avenues for future research into this common psychiatric condition.