Genome-wide association studies for canine hip dysplasia in single and multiple populations – implications and potential novel risk loci

Abstract

Background Association mapping studies of quantitative trait loci (QTL) for canine hip dysplasia (CHD) can contribute to the understanding of the genetic background of this common and debilitating disease and might contribute to its genetic improvement. The power of association studies for CHD is limited by relatively small sample numbers for CHD records within countries, suggesting potential benefits of joining data across countries. However, this is complicated due to the use of different scoring systems across countries. In this study, we incorporated routinely assessed CHD records and genotype data of German Shepherd dogs from two countries (UK and Sweden) to perform genome-wide association studies (GWAS) within populations using different variations of CHD phenotypes. As phenotypes, dogs were either classified into cases and controls based on the Fédération Cynologique Internationale (FCI) five-level grading of the worst hip or the FCI grade was treated as an ordinal trait. In a subsequent meta-analysis, we added publicly available data from a Finnish population and performed the GWAS across all populations. Genetic associations for the CHD phenotypes were evaluated in a linear mixed model using 62,089 SNPs. Results Multiple SNPs with genome-wide significant and suggestive associations were detected in single-population GWAS and the meta-analysis. Few of these SNPs overlapped between populations or between single-population GWAS and the meta-analysis, suggesting that many CHD-related QTL are population-specific. More significant or suggestive SNPs were identified when FCI grades were used as phenotypes in comparison to the case-control approach. MED13 (Chr 9) and PLEKHA7 (Chr 21) emerged as novel positional candidate genes associated with hip dysplasia. Conclusions Our findings confirm the complex genetic nature of hip dysplasia in dogs, with multiple loci associated with the trait, most of which are population-specific. Routinely assessed CHD information collected across countries provide an opportunity to increase sample sizes and statistical power for association studies. While the lack of standardisation of CHD assessment schemes across countries poses a challenge, we showed that conversion of traits can be utilised to overcome this obstacle.

Identification of Genetic Risk Factors for Monogenic and Complex Canine Diseases

“…Among British-, Finnish-, and Swedish-based German shepherd dogs, CHD was studied within single geography-restricted populations as well as by meta-analysis. Although five associations were identified, including those within proximity to genes MED13 and PLEKHA7 (115), none of the associated loci overlapped between single populations (116). Further discordance among genetic association studies is documented (114)(115)(116)(117)(118)(119)(120)(121)(122).…”

“…Although five associations were identified, including those within proximity to genes MED13 and PLEKHA7 (115), none of the associated loci overlapped between single populations (116). Further discordance among genetic association studies is documented (114)(115)(116)(117)(118)(119)(120)(121)(122). Discrepancies between association studies have led to the view that CHD is strongly influenced by the genomic architectures of affected populations, though surely other confounding variables, such as CHD screening methodology, age, neuter status, and obesity, could be at play.…”

Pelvic osteotomy techniques in the management of canine hip dysplasia – evolution of the treatment paradigm

“…This has led to more sublime patient qualification criteria for surgery and also to a lower rate of complication rates as a result (35). The genetic background has recently been widely investigated and the latest data strongly indicates the complex genetic nature of hip dysplasia in dogs, with multiple loci being associated with the trait, most of which are population-specific (41). There are also substantial signs that indicate the existence of partially distinct loci and genes or pathways in the development of incongruity, mild dysplasia, moderateto-severe dysplasia and osteoarthritis of the canine hip Pelvic osteotomy techniques in the management of canine hip dysplasia -evolution of the treatment paradigm joints (22,23,41).…”

“…The genetic background has recently been widely investigated and the latest data strongly indicates the complex genetic nature of hip dysplasia in dogs, with multiple loci being associated with the trait, most of which are population-specific (41). There are also substantial signs that indicate the existence of partially distinct loci and genes or pathways in the development of incongruity, mild dysplasia, moderateto-severe dysplasia and osteoarthritis of the canine hip Pelvic osteotomy techniques in the management of canine hip dysplasia -evolution of the treatment paradigm joints (22,23,41). The fundamental stabilizer of the coxofemoral joint consists of the ligament of the head of the femur, the joint capsule and the dorsal acetabular rim (DAR).…”

Mechanical osteoarthritis of the hip in a one medicine concept: a narrative review

“…The pathogenesis of dog OA closely resembles the primary disease in humans [ 11 ], despite many questions remaining unanswered regarding this poorly understood entity [ 9 , 10 ]. Some genome-wide association studies in dogs identified single nucleotide polymorphisms that were linked with canine HD [ 12 , 13 ] and the intronic deletion in the fibrillin-2 gene in the fibrous joint capsule was associated with canine hip laxity [ 13 ]. Similar studies were performed in humans and several genes were found to be related to HD development, such as CX3CR1 [ 14 ], GDF5 [ 15 ] and CTBP2 [ 16 ].…”