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Array Comparative Genomic Hybridization Array CGH for Detection of Genomic Copy Number Variants
Published on: February 21, 2015
Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number
Matthew J Gazzellone1, Mehdi Zarrei1, Christie L Burton2
1The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON Canada.
Insights
Rare copy number variations (CNVs) may play a role in childhood-onset obsessive-compulsive disorder (OCD). This study identified specific CNVs in pediatric OCD cases, suggesting a genetic link to the disorder's development.
Area of Science:
- Genetics
- Neuroscience
- Pediatric Disorders
Background:
- Obsessive-compulsive disorder (OCD) is a complex neuropsychiatric condition with a known genetic influence.
- Childhood-onset OCD presents differently from adult-onset OCD, with higher male prevalence and heritability.
- Copy number variations (CNVs) are implicated in various neuropsychiatric disorders, prompting investigation into their role in OCD.
Purpose of the Study:
- To investigate the potential contribution of rare copy number variations (CNVs) to the etiology of pediatric obsessive-compulsive disorder (OCD).
- To identify specific CNVs in children with idiopathic OCD compared to population controls.
Main Methods:
- Genotyping of 307 unrelated pediatric OCD probands and 3861 population controls.
- Identification of rare CNVs (frequency <0.5%, size ≥15 kb).
- Analysis of parent-child trios to detect de novo CNVs and exome sequencing for additional mutations.
Main Results:
- De novo CNVs were identified in 2.3% of pediatric OCD probands.
- Enrichment of CNVs in genes targeted by the fragile X mental retardation protein was observed, similar to autism and schizophrenia.
- CNVs affecting genes involved in neuronal migration, synapse formation, and postsynaptic scaffolding were identified, along with CNVs at known genomic disorder loci.
- The gene BTBD9 was identified as a candidate for OCD, and a mutation in DRD4 was found in one trio.
Conclusions:
- Rare CNVs represent a potential contributing factor to the genetic etiology of obsessive-compulsive disorder.
- Specific CNVs and genes identified may offer insights into OCD pathogenesis.
- Further research into CNVs in OCD is warranted.
Background:
Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD.
Methods:
We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD.
Results:
We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal p = 1.85 × 10-03; FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten "CNV positive" trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in DRD4.
Conclusions:
Our findings suggest that rare CNVs may contribute to the etiology of OCD.
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