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.

中文翻译：

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单个和多个人群中犬髋关节发育不良的全基因组关联研究——影响和潜在的新风险位点

犬髋关节发育不良 (CHD) 数量性状位点 (QTL) 的关联作图研究有助于了解这种常见且使人衰弱的疾病的遗传背景，并可能有助于其遗传改良。CHD 关联研究的力量受到国家内 CHD 记录相对较小的样本数量的限制，这表明连接各国数据的潜在好处。然而，由于各国使用不同的评分系统，这很复杂。在这项研究中，我们纳入了来自两个国家（英国和瑞典）的德国牧羊犬的常规评估的 CHD 记录和基因型数据，以使用不同的 CHD 表型变异在人群中进行全基因组关联研究 (GWAS)。作为表型，狗要么根据国际犬类联合会 (FCI) 最差髋关节的五级分级分为病例和对照，要么将 FCI 等级视为序数性状。在随后的荟萃分析中，我们添加了来自芬兰人群的公开数据，并对所有人群进行了 GWAS。使用 62,089 个 SNP 在线性混合模型中评估了 CHD 表型的遗传关联。在单一群体 GWAS 和荟萃分析中检测到多个具有全基因组显着性和暗示性关联的 SNP。这些 SNP 很少在群体之间或单一群体 GWAS 和荟萃分析之间重叠，这表明许多与 CHD 相关的 QTL 是群体特异性的。与病例对照方法相比，当使用 FCI 等级作为表型时，发现了更显着或提示性的 SNP。MED13（第 9 组）和 PLEKHA7（第 21 组）成为与髋关节发育不良相关的新位置候选基因。我们的研究结果证实了狗髋关节发育不良的复杂遗传性质，具有与该性状相关的多个位点，其中大多数是群体特异性的。定期评估的各国收集的先心病信息为增加关联研究的样本量和统计能力提供了机会。虽然各国冠心病评估方案缺乏标准化构成了挑战，但我们表明可以利用特征转换来克服这一障碍。