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.