title: 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.
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.forename: Ernest T
authors.initials: ET
authors.lastname: Lam
authors.forename: Alison L
authors.initials: AL
authors.lastname: Ruhe
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Erdman
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Robertson
authors.forename: Aubrey A
authors.initials: AA
authors.lastname: Webb
authors.forename: D Colette
authors.initials: DC
authors.lastname: Williams
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Chang
authors.forename: Marjo K
authors.initials: MK
authors.lastname: Hytönen
authors.forename: Hannes
authors.initials: H
authors.lastname: Lohi
authors.forename: Steven P
authors.initials: SP
authors.lastname: Hamilton
authors.forename: Mark W
authors.initials: MW
authors.lastname: Neff
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D003051:Cochlea / Q000254:growth & development / Q000473:pathology; D015834:Cochlear Diseases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003638:Deafness / Q000235:genetics / Q000662:veterinary; D004285:Dogs; D010450:Endopeptidases / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D016328:NF-kappa B / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044767:Ubiquitin-Protein Ligases; D064570:Ubiquitin-Specific Proteases
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; C098584:RBBP6 protein, human; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C579220:USP31 protein, human; D064570:Ubiquitin-Specific Proteases