Background: Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population. While highly heritable, complex genetics has hampered attempts to elucidate OCD etiology. Dogs suffer from naturally occurring compulsive disorders that closely model human OCD, manifested as an excessive repetition of normal canine behaviors that only partially responds to drug therapy. The limited diversity within dog breeds makes identifying underlying genetic factors easier.Results: We use genome-wide association of 87 Doberman Pinscher cases and 63 controls to identify genomic loci associated with OCD and sequence these regions in 8 affected dogs from high-risk breeds and 8 breed-matched controls. We find 119 variants in evolutionarily conserved sites that are specific to dogs with OCD. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Four genes, all with synaptic function, have the most case-only variation: neuronal cadherin (CDH2), catenin alpha2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP). In the 2 Mb gene desert between the cadherin genes CDH2 and DSC3, we find two different variants found only in dogs with OCD that disrupt the same highly conserved regulatory element. These variants cause significant changes in gene expression in a human neuroblastoma cell line, likely due to disrupted transcription factor binding.Conclusions: The limited genetic diversity of dog breeds facilitates identification of genes, functional variants and regulatory pathways underlying complex psychiatric disorders that are mechanistically similar in dogs and humans.
Bibliographical noteFunding Information:
We thank all the dog owners, breeders, and breed clubs, as well as the veterinarians in the US and Sweden for providing us with blood samples. This work was supported by a SPARC grant from the Broad Institute, Uppsala University, Medical Research Council, and a grant from NIMH/NIH (R01MH081201), and by funds from the Poitras Center for Affective Disorders Research to GF. KLT is the recipient of a EURYI from the European Science Foundation. EKK is supported by fellowships from the American Cancer Society and the Charles A King Trust. We thank Andy Reynolds for help with genotype calling, Evan Mauceli for help with genotyping concordance analysis, Jeremy Johnson for project management assistance, Tarjei Mikkelsen and Xiaolan Zhang for supplying reagents for the luciferase assays, and Leslie Gaffney for help with illustration. We thank Kate Meurs and Åke Hedhammar for their work on sample collection. Our deepest appreciation goes to Nicholas Dodman, veterinary behaviorist and professor at Tufts University, and animal behaviorist Alice Moon-Fanelli, who performed extensive and careful phenotyping of OCD in the Doberman pinscher GWAS sample set using methodologies developed by Dr. Dodman and his group. This careful phenotyping, described in the earlier published GWAS study , provided a foundation for the work described herein. We also acknowledge the valuable material and intellectual contributions of Drs. Edward Ginns and Marzena Galdzicka to this study.