A genome-wide association study of deafness in three canine breeds

Abstract

Congenital deafness in the domestic dog is usually related to the presence of white pigmentation, which is controlled primarily by the piebald locus on chromosome 20 and also by merle on chromosome 10. Pigment-associated deafness is also seen in other species, including cats, mice, sheep, alpacas, horses, cows, pigs, and humans, but the genetic factors determining why some piebald or merle dogs develop deafness while others do not have yet to be determined. Here we perform a genome-wide association study (GWAS) to identify regions of the canine genome significantly associated with deafness in three dog breeds carrying piebald: Dalmatian, Australian cattle dog, and English setter. We include bilaterally deaf, unilaterally deaf, and matched control dogs from the same litter, phenotyped using the brainstem auditory evoked response (BAER) hearing test. Principal component analysis showed that we have different distributions of cases and controls in genetically distinct Dalmatian populations, therefore GWAS was performed separately for North American and UK samples. We identified one genome-wide significant association and 14 suggestive (chromosome-wide) associations using the GWAS design of bilaterally deaf vs. control Australian cattle dogs. However, these associations were not located on the same chromosome as the piebald locus, indicating the complexity of the genetics underlying this disease in the domestic dog. Because of this apparent complex genetic architecture, larger sample sizes may be needed to detect the genetic loci modulating risk in piebald dogs.

Fig 1. PCA of dog samples.

(A) Dalmatians, (B) Australian cattle dogs, and (C) English setters from North America (triangles) and UK (circles). Bilaterally deaf dog samples are shown in red, unilaterally deaf dogs in blue, and control dogs in black.

Fig 2. Manhattan, QQ and LD plots of the significant association using bilaterally deaf vs. control Australian cattle dogs.

(A) Manhattan plot. Red line shows the Bonferroni correction P-value threshold calculated on unlinked SNPs. The permutation threshold is beyond the y axis, at 1.5x10^-9. (B) QQ plot with inflation factor (λ) shown. (C) LD plot zoomed in on the region surrounding the significant association. Colors indicate the amount of LD with the most associated SNP, ranging from red (r²>0.8) to black (r²<0.2).