New genetic findings may lead to better interventional therapies for obsessive compulsive disorders

University of Massachusetts Medical SchoolJan 7 2010

A collaboration between the University of Massachusetts Medical School, the Cummings School of Veterinary Medicine at Tufts University and the Broad Institute at the Massachusetts Institute of Technology has identified a genetic locus on canine chromosome 7 which coincides with an increased risk of obsessive compulsive disorder (OCD) susceptibility. The findings, published in the January 2010 edition of Molecular Psychiatry, suggest that particular genetic proteins may possibly influence central nervous system development and increase the risk of OCD.

Characterized by time-consuming, repetitive behaviors, OCD affects roughly 2 percent of humans. Meanwhile, the equally distressing canine equivalent, canine compulsive disorder (CCD), is more prevalent in certain dog breeds, especially Dobermans and Bull Terriers.

For more than a decade, animal behaviorists Nicholas Dodman, BVMS, MRCVS, professor of clinical sciences, and Alice Moon-Fanelli, PhD, clinical assistant professor, at the Cummings School of Veterinary Medicine at Tufts, collected blood samples from carefully characterized Doberman patients exhibiting flank- and/or blanket-sucking compulsive behaviors, as well as healthy, unaffected Dobermans. In 2001, Edward Ginns, MD, PhD, director of the Program in Medical Genetics at UMass Medical School, joined the effort, enabling genetic studies that culminated in the genome wide association study that began in 2007 using the canine Affymetrix genotyping array at the Broad Institute.

The chromosome 7 location most significantly associated with CCD is located within the neural cadherin-2 gene, CDH2. CDH2 is widely expressed, mediating synaptic activity-calcium flux related neuronal adhesion. Dogs showing multiple compulsive behaviors had a higher frequency of the "risk" associated DNA sequence than dogs with a less severe phenotype (60 and 43 percent, respectively, compared with 22 percent in unaffected dogs). This association of CCD with the CDH2 gene region on chromosome 7 is the first genetic locus identified for any animal compulsive disorder. The neural cadherin-2 gene, CDH2, is an especially attractive candidate disease gene as it is involved in mediating presynaptic to postsynaptic neuronal junction adhesion, neuronal axon outgrowth and guidance in the central nervous system during development when critical brain nerve networks are established. Discovery of this locus raises the intriguing possibility that CDH2, and other neuronal adhesion proteins, are involved in human compulsive behaviors, including those observed in autism spectrum disorder.

"The CDH2 gene is expressed in the hippocampus, a brain region suspected to be involved in OCD," said Dodman, the study's lead author. "Additionally, this gene oversees structures and processes that are possibly instrumental in propagating compulsive behaviors - for example, the formation and proper functioning of glutamate receptors." Dodman added that "this finding is congruent with current evidence that N-methyl-D-aspartate (NMDA) blockers are effective in the treatment of OCD."

"The occurrence of repetitive behaviors and similarities in response to drug treatments in both canine CCD and human OCD suggest that common pathways are involved," said Ginns. "We are hopeful that these finding will lead to a better understanding of the biology of compulsive disorder and facilitate development of genetic tests, enabling earlier interventions and even treatment or prevention of compulsive disorders in at-risk canines and humans."