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.

Keywords: BVA/KC scores; FCI grades; Genetic diversity; German shepherd dogs; QTL.

Fig. 1

Principal component analysis for meta-analysis of the pruned genomic data. Eigenvalues for the first two principal components are plotted and dogs are coloured according to their population

Fig. 2

Manhattan plots for all CHD phenotype approaches in single-population and meta-analysis GWAS. The Finnish-population and meta-analysis GWAS are based on data provided by Mikkola et al. [11] and the Finnish-population GWAS is a repetition of the original GWAS with altered phenotypes. Manhattan plots were produced for the GWAS in UK (n = 180), Swedish (n = 402) and Finnish (n = 775) German Shepherd dog populations and for the meta-analysis GWAS (n = 1357). Genome-wide significance level is indicated by the red line and a suggestive association by the blue line