Abstract
Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3–5 years) than typically expected for aging dogs (8–10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09×10−13). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS–guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.
Highlights
Age-related hearing loss occurs in humans with a prevalence of about 40% in individuals older than 65 years of age
Adultonset deafness in Border Collies typically begins in early adulthood and is similar to age-related hearing loss in humans
We identified three genetic variants that were strongly associated with adult-onset deafness in a sample of 405 Border Collies
Summary
Age-related hearing loss (presbycusis) occurs in humans with a prevalence of about 40% in individuals older than 65 years of age. It is associated with difficulties of communication, isolation, depression and possibly even dementia in the severely affected [1]. There are extensive genetic contributions to hearing variation [2], which has an estimated heritability of 35–55% (reviewed in [3]). A recent genome-wide association study (GWAS) performed in an isolated Finnish population identified the candidate gene IQ motif containing GTPase activating protein 2 (IQGAP2) as a novel risk locus for hearing loss [6], as well as modest support for another, previously identified GWAS candidate, metabotropic glutamate receptor 7 (GRM7) [7]. The breadth of genetic variation that may confer risk for this common disorder remains unknown
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