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. 2016 Oct 18:8:36.
doi: 10.1186/s11689-016-9170-9. eCollection 2016.

Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation

Matthew J Gazzellone #  1 , Mehdi Zarrei #  1 , Christie L Burton  2 , Susan Walker  1 , Mohammed Uddin  1 , S M Shaheen  2   3 , Julie Coste  2 , Rageen Rajendram  2   4 , Reva J Schachter  2 , Marlena Colasanto  2 , Gregory L Hanna  5 , David R Rosenberg  6   7 , Noam Soreni  8 , Kate D Fitzgerald  5 , Christian R Marshall  1 , Janet A Buchanan  1 , Daniele Merico  1 , Paul D Arnold  2   3   9 , Stephen W Scherer  1   10
Affiliations

Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation

Matthew J Gazzellone et al. J Neurodev Disord. .

Abstract

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.

Keywords: Copy number variation; Obsessive-compulsive disorder; Pediatrics; Whole-exome sequencing.

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References

    1. Pauls DL, Abramovitch A, Rauch SL, Geller DA. Obsessive-compulsive disorder: an integrative genetic and neurobiological perspective. Nat Rev Neurosci. 2014;15(6):410–424. doi: 10.1038/nrn3746. - DOI - PubMed
    1. Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15(1):53–63. doi: 10.1038/mp.2008.94. - DOI - PMC - PubMed
    1. Leckman JF, Denys D, Simpson HB, Mataix-Cols D, Hollander E, Saxena S, et al. Obsessive-compulsive disorder: a review of the diagnostic criteria and possible subtypes and dimensional specifiers for DSM-V. Depress Anxiety. 2010;27(6):507–527. doi: 10.1002/da.20669. - DOI - PMC - PubMed
    1. Anholt GE, Aderka IM, van Balkom AJ, Smit JH, Schruers K, van der Wee NJ, et al. Age of onset in obsessive-compulsive disorder: admixture analysis with a large sample. Psychol Med. 2014;44(1):185–194. doi: 10.1017/S0033291713000470. - DOI - PubMed
    1. Stewart SE, Geller DA, Jenike M, Pauls D, Shaw D, Mullin B, et al. Long-term outcome of pediatric obsessive-compulsive disorder: a meta-analysis and qualitative review of the literature. Acta Psychiatr Scand. 2004;110(1):4–13. doi: 10.1111/j.1600-0447.2004.00302.x. - DOI - PubMed