Variation in Genes Related to Cochlear Biology Is Strongly Associated with Adult-Onset Deafness in Border Collies

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.

The Genetics of Deafness in Domestic Animals

“…The loss had begun at about 5 years of age, which ruled out presbycusis as a likely cause, and several had been BAER tested as hearing at earlier ages. The loss was gradual, had no gender predilection, and appeared to follow an AD pattern ( 146 , 147 ).…”

Insights into Morphology and Disease from the Dog Genome Project

“…By most accounts, the use of GWAS to locate heritable traits has been wildly successful in dogs, identifying loci for eye diseases, skin disorders, cancer, deafness, neurological disorders, heart disease, and a host of other disorders (Ahonen et al 2013, Grall et al 2012, Karyadi et al 2013, Olsson et al 2011, Tengvall et al 2013, Yokoyama et al 2012), as well as morphological traits (Boyko et al 2010, Vaysse et al 2011), including body size, skull shape, leg length, and fur type and color (Cadieu et al 2009, Clark et al 2006, Dreger et al 2013, Drögemüller et al 2008, Karlsson et al 2007, Parker et al 2009, Rimbault et al 2013, Schoenebeck et al 2012). Loci of large effect, a fraction of which are described below, were rapidly identified in population-based approaches that compared SNP allele frequencies with a myriad of phenotypic traits.…”

An analysis of the inheritance pattern of an adult-onset hearing loss in Border Collie dogs

“…Although BAER hearing tests can be used to diagnose dogs with reduced hearing to an advanced stage and complete deafness, no diagnostic test is currently available for early identification of those Border Collies likely to become deaf. A recent study using some of the dogs reported here, but assuming an autosomal mode of inheritance and an earlier age of onset, and a GWAS approach, reported a region on CFA6 that appeared to be implicated [ 3 ]. An earlier smaller GWAS by some members of this group suggested a region on CFA18 [ 4 ].…”