Investigation of complex neuropsychiatric disorders in the domestic dog: Genome-wide surveys for loci underlying noise phobia and adult-onset deafness in purpose-bred dogs.

摘要

The domestic dog offers a novel and potentially powerful genetic model for studies of complex neuropsychiatric disease, including maladaptive behavioral conditions analogous to human psychiatric disorders. Dogs provide two critical advantages that facilitate such studies: (a) potentially prominent genetic homogeneity due to the foundations of individual breeds; and (b) naturally occurring behavioral disorders with clinical features similar to a number of human anxiety disorders (e.g., separation anxiety, obsessive-compulsive disorder, specific phobias). After establishing the validity of the dog as a genetic model for studying neuropsychiatric disorders relevant to human conditions, I will present work conducted in the context of our laboratory's on-going project in canine behavioral genetics. Specifically, we have conducted the first genetic study of the canine anxiety disorder noise phobia, and the first genome-wide association study for adult-onset deafness in dogs. We have identified multiple candidate regions in Border collies that may confer risk for noise phobia, including loci on Canis familiaris chromosome (CFA) 5, CFA8 and two loci on CFA10 that all appear to demonstrate epistatic interactions. We have also identified a strong association region on CFA6 for adult-onset deafness in Border collies. Targeted next-generation sequencing of the CFA6 deafness locus identified multiple candidate sequence variants, including non-synonymous SNPs in putative genes USP31 and RBBP6. Together, these findings implicate new potential risk loci for troubling disorders, with implications for further research in larger samples of dogs of different breeds. Additionally, our results highlight the strong potential for studies of complex neuropsychiatric disease in the dog that may be directly relevant for analogous disorders in human populations, providing new opportunities for scientific discovery.