Division of Genetics and Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, EH25 9RG, UK.
Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, PO Box 7023, S-750 07, Uppsala, Sweden.
BMC Genomics. 2021 Sep 2;22(1):636. doi: 10.1186/s12864-021-07945-z.
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.
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.
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.
犬髋关节发育不良（CHD）的数量性状基因座（QTL）关联研究有助于了解这种常见且衰弱性疾病的遗传背景，并可能有助于其遗传改良。由于各国 CHD 记录的样本数量相对较少，关联研究对 CHD 的作用有限，这表明跨国数据联合可能会带来益处。然而，由于各国使用不同的评分系统，这变得复杂。在这项研究中，我们整合了来自两个国家（英国和瑞典）的德国牧羊犬的常规评估 CHD 记录和基因型数据，在不同的 CHD 表型变化下，在种群内进行全基因组关联研究（GWAS）。作为表型，狗要么根据国际犬业联合会（FCI）的五级髋关节最差分级分为病例和对照，要么将 FCI 分级视为有序性状。在随后的荟萃分析中，我们添加了芬兰人群中公开可用的数据，并在所有人群中进行了 GWAS。使用 62089 个 SNP，在线性混合模型中评估了 CHD 表型的遗传关联。
在单种群 GWAS 和荟萃分析中，检测到多个具有全基因组显著和提示意义的关联 SNP。这些 SNP 中很少在种群之间或在单种群 GWAS 和荟萃分析之间重叠，表明许多 CHD 相关 QTL 是特定于种群的。与病例对照方法相比，当 FCI 分级用作表型时，鉴定出更多的显著或提示性 SNP。MED13（9 号染色体）和 PLEKHA7（21 号染色体）作为与髋关节发育不良相关的新定位候选基因出现。
我们的研究结果证实了犬髋关节发育不良的复杂遗传性质，多个与该性状相关的位点，其中大多数是特定于种群的。在跨国收集的常规评估 CHD 信息为增加关联研究的样本量和统计效力提供了机会。虽然各国之间 CHD 评估方案缺乏标准化构成了挑战，但我们表明可以利用性状转换来克服这一障碍。
