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.

A Missense Mutation in the KLF7 Gene Is a Potential Candidate Variant for Congenital Deafness in Australian Stumpy Tail Cattle Dogs

“…Several homozygous wild type individuals were detected among the deaf ASCDs suggesting additional genetic risk factors. This was not surprising, as canine congenital deafness seems to be a complex disorder and different regions were detected in other GWASs for deafness so far [ 17 ].…”

“…In our study, more than half of the significant associated SNPs (7 out of 13) were located on CFA37, including the most significantly related SNP (chr37:44793, p = 9.54 × 10 − 21 ). In a recent study of Dalmatian deafness, signals were also detected in this region [ 17 ]. However, there was no associated peak on CFA37 reported in the previous microsatellite-based study in ASCD.…”

“…However, within a potential candidate gene Sry-related Hmg-box gene 10 ( SOX10 ) located in this region, no causative alterations were detected. A recent genome-wide association study (GWAS) reported 14 chromosomes that were significantly associated with deafness in three canine breeds, and CFA3 was significantly associated with bilateral deafness in Australian Cattle Dogs [ 17 ]. In this study, three suggestive candidate genes near significantly associated regions were detected in these three dog breeds, including ATPase Na + /K + Transporting Subunit Alpha 4 ( ATP1A4 ), Transformation/Transcription Domain Associated Protein ( TRRAP ), and Potassium Inwardly Rectifying Channel Subfamily J Member 10 ( KCNJ10 ) [ 17 ].…”

STRING data mining of GWAS data in canine hereditary pigment-associated deafness

“…Foundational data for the study came from a GWAS of 502 deaf and hearing dogs (Australian cattle dogs, Dalmatians, English setters) ( Hayward et al, 2020 ). An initial candidate list of 400 genes was assembled from (1) genes located within 500 kb of single nucleotide polymorphisms (SNPs) from our previous GWAS that had approached significance (235 genes), (2) pigmentation genes (31 genes) ( UniProt Consortium, 2019 ), (3) genes identified in humans as responsible for non-syndromic autosomal recessive and dominant deafness (113 genes) ( Van Camp and Smith, 2020 ), and (4) genes identified from proteomic studies of mouse cochlear inner hair cells and rat stria vascularis tissues that were also located near our GWAS SNPs (21 genes) ( Hickox et al, 2017 ; Uetsuka et al, 2015 ).…”

“…The mechanism of inheritance does not appear to be simple Mendelian. Genome wide association studies (GWAS) and other molecular genetic studies of deafness by our lab and others have failed to identify loci significantly associated with deafness ( Cargill, 2004 ; Kluth and Distl, 2013 ; Stritzel et al., 2009 ; Sommerlad et al., 2010 ; Hayward et al, 2020 ), a common outcome with complex disorders ( Altshuler et al., 2008 ; Rudy, 2012 ). Numerous specific candidate genes have been ruled out: EDNRB and KIT ( Metallinos and Rine, 2000 ), MYO15A ( Rak et al., 2002 ), PAX3 ( Brenig et al., 2003 ), TMC1 and TMIE ( Mieskes and Distl, 2006 ), SILV ( Stritzel et al., 2007 ), and ESPN, MYO3A, SLC26A5 , and USH1C ( Mieskes and Distl, 2007 ).…”