Whole genome analyses reveal significant convergence in obsessive-compulsive disorder between humans and dogs

Abstract

Obsessive-compulsive disorder (OCD) represents a heterogeneous collection of diseases with diverse levels of phenotypic, genetic, and etiologic variability, making it difficult to identify the underlying genetic and biological mechanisms in humans. Domestic dogs exhibit several OCD-like behaviors. Using continuous circling as a representative phenotype for OCD, we screened two independent dog breeds, the Belgian Malinois and Kunming Dog and subsequently sequenced ten circling dogs and ten unaffected dogs for each breed. Using population differentiation analyses, we identified 11 candidate genes in the extreme tail of the differentiated regions between cases and controls. These genes overlap significantly with genes identified in a genome wide association study (GWAS) of human OCD, indicating strong convergence between humans and dogs. Through gene expressional analysis and functional exploration, we found that two candidate OCD risk genes, PPP2R2B and ADAMTSL3, affected the density and morphology of dendritic spines. Therefore, changes in dendritic spine may underlie some common biological and physiological pathways shared between humans and dogs. Our study revealed an unprecedented level of convergence in OCD shared between humans and dogs, and highlighted the importance of using domestic dogs as a model species for many human diseases including OCD.

Keywords: Circling behavior; Domestic dogs; Genetic convergence; Obsessive-compulsive disorder; Whole genome sequencing.