Genomic Risk for Severe Canine Compulsive Disorder, a Dog Model of Human OCD.

Dogs naturally suffer the same complex diseases as humans, including mental illness. The dog is uniquely suited as a model organism to explore the genetics of neuropsychiatric disorders. Historical breed demographics have enriched purebred populations for founder effect mutations with tractable architectures, making genotypic analyses advantageous. Over a pet's lifetime, owners observe the animal's stress tolerance, arousal, and anxiety, and can inform on rich behavioral profiles for phenotypic analyses. Here we leverage these strengths in a search for inherited fac-tors that exacerbate canine compulsive disorder (CCD), the dog counterpart to human obsesssive compulsive disorder (OCD). Our rationale is that identifying pathways that predispose to disease severity will expand therapeutic options, and ultimately bring relief to those patients suffering the most. We have performed a GWAS of purebred Doberman pinschers that compares severely affected cases to moderately affected cases (24:70). This GWAS identified two statistically sig-nificant risk loci, on CFA34 and CFA11, and a third with suggestive evidence on CFA16. The locus on CFA34 includes a cluster of 5-HT3 receptor genes (HTR3C, HTR3D, and HTR3E) that implicate a serotonergic pathway that is routinely targeted by anti-OCD medications. The locus on CFA11 is syntenic with human CTXN3-SLC12A2 (5q35.1), an inherited risk factor for schiz-ophrenia. The third locus harbors teneurin-3 (TENM3), a modulator of the hypothalamic-pituitary-adrenal (HPA) axis, with effects on stress tolerance and stress-related behavior. We dis-cuss candidate genes and putative functional variants in light of pharmacological responsiveness, psychiatric comorbidity, and the potential for gene-by-environment interactions in the genetic etiology of OCD and CCD. [ABSTRACT FROM AUTHOR]