Genome-Wide Association Study of Age-Related Hearing Loss in CFW Mice Identifies Multiple Genes and Loci, Including Prkag2.

Purpose: Age-related hearing loss (ARHL) is one of the most prevalent conditions affecting the elderly. ARHL is influenced by a combination of environmental and genetic factors; the identification of the genes that confer risk will aid in the prevention and treatment of ARHL. The mouse and human inner ears are functionally and genetically homologous. We used Carworth Farms White (CFW) mice to study the genetic basis of ARHL because they are genetically diverse and exhibit variability in the age of onset and severity of ARHL.

Methods: Hearing at a range of frequencies was measured using auditory brainstem response (ABR) thresholds in 946 male and female CFW mice at the age of 1, 6, and 10 months. We genotyped the mice using low-coverage (mean coverage 0.27 ×) whole-genome sequencing (lcWGS) followed by imputation using STITCH. To determine the accuracy of the genotypes, we sequenced 8 samples at > 30 × coverage and used those data to estimate the accuracy of lcWGS genotyping, which was > 99.5%. We performed a genome-wide association study (GWAS) for the ABR thresholds for each frequency at each age, and we also performed a GWAS for age at deafness.

Results: We obtained genotypes at 4.18 million single nucleotide polymorphisms (SNP). The SNP heritability for traits ranged from 0 to 42%. GWAS identified 10 significant associations with ARHL that contained potential candidate genes, including Dnah11, Rapgef5, Cpne4, Prkag2, and Nek11. Genetic ablation of Prkag2 caused ARHL at high frequencies, strongly suggesting that Prkag2 is the causal gene for one of the associations.

Conclusions: GWAS for ARHL in CFW outbred mice identified genetic risk factors for ARHL, including Prkag2. Our results will help to define novel therapeutic targets for the treatment and prevention of this common disorder.