Abstract
The recent finding that the neuronal cadherin gene CDH2 confers a highly significant risk for canine compulsive disorder led us to investigate whether missense variants within the human ortholog CDH2 are associated with altered susceptibility to obsessive-compulsive disorder (OCD), Tourette disorder (TD) and related disorders. Exon resequencing of CDH2 in 320 individuals identified four non-synonymous single-nucleotide variants, which were subsequently genotyped in OCD probands, Tourette disorder probands and relatives, and healthy controls (total N=1161). None of the four variants was significantly associated with either OCD or TD. One variant, N706S, was found only in the OCD/TD groups, but not in controls. By examining clinical data, we found there were significant TD-related phenotype differences between those OCD probands with and without the N845S variant with regard to the co-occurrence of TD (Fisher’s exact test P=0.014, OR=6.03). Both N706S and N845S variants conferred reduced CDH2 protein expression in transfected cells. Although our data provide no overall support for association of CDH2 rare variants in these disorders considered as single entities, the clinical features and severity of probands carrying the uncommon non-synonymous variants suggest that CDH2, along with other cadherin and cell adhesion genes, is an interesting gene to pursue as a plausible contributor to OCD, TD and related disorders with repetitive behaviors, including autism spectrum disorders.
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Acknowledgements
We are indebted to Diane Kazuba and Brenda Justement for conducting proband interviews, to Teresa Tolliver and Su-Jan Huang for excellent technical assistance in DNA extraction and general lab assistance and to Theresa DeGuzman for development of the OCD phenotype database and editing and graphical assistance with this manuscript. GA Heiman, RA King and JA Tischfield are supported by grants from the New Jersey Center for Tourette Syndrome and Associated Disorders and NIMH (R01MH092293). Support for the experimental studies was from the NIMH Intramural Research Program and a grant from the Simons Foundation (LF Reichardt).
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JRW is a Senior Principal Scientist, Pharma Research and Early Development at F Hoffmann-La Roche Ltd. None of the other authors has anything to disclose.
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Moya, P., Dodman, N., Timpano, K. et al. Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes. Eur J Hum Genet 21, 850–854 (2013). https://doi.org/10.1038/ejhg.2012.245
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DOI: https://doi.org/10.1038/ejhg.2012.245
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