Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder
- Equal contributors
1 Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA
2 McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
3 Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
4 College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
5 Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
6 Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Van Etten B06, Bronx, NY 10461, USA
7 Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
8 Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala 75237, Sweden
9 Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
Genome Biology 2014, 15:R25 doi:10.1186/gb-2014-15-3-r25Published: 14 March 2014
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.
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.
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.