Abstract
BackgroundObsessive-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.ResultsWe 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.ConclusionsThe 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.
Highlights
Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population
Genome-wide association studies and homozygosity mapping Using the raw data from the genome-wide association study (GWAS) by Dr Dodman and collaborators [14], which included 92 Doberman Pinscher (DP) cases and 68 DP controls extensively phenotyped for canine OCD, we reanalyzed the Affymetrix genotype intensity data with a new calling algorithm, MAGIC [15]
We tested all Gene Ontology (GO) gene sets with 5 to 1,000 genes (5,206 sets) for enrichment in the new GWAS regions using INRICH, a permutation based software that rigorously controls for region size, SNP density, and gene size and gene number [17]
Summary
Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population. 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. Obsessive compulsive disorder (OCD) is a common (1 to 3% of the population) and debilitating neuropsychiatric disorder characterized by persistent intrusive thoughts and time-consuming repetitive behaviors [1]. Artificial mouse models have proven more effective for elucidating the neural pathways underlying OCD-like behaviors. Resequencing of exons of DLGAP3 (the human SAPAP3 gene) revealed excessive rare non-synonymous variants in human OCD and trichotillomania individuals [7]
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