Huang Meng, Hayward Jessica J, Corey Elizabeth, Garrison Susan J, Wagner Gabriela R, Krotscheck Ursula, Hayashi Kei, Schweitzer Peter A, Lust George, Boyko Adam R, Todhunter Rory J
Department of Crop and Soil Science, Washington State University, Pullman, Washington, United States of America.
Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America.
PLoS One. 2017 Jun 14;12(6):e0176932. doi: 10.1371/journal.pone.0176932. eCollection 2017.
Hip dysplasia (HD), elbow dysplasia (ED), and rupture of the cranial (anterior) cruciate ligament (RCCL) are the most common complex orthopedic traits of dogs and all result in debilitating osteoarthritis. We reanalyzed previously reported data: the Norberg angle (a quantitative measure of HD) in 921 dogs, ED in 113 cases and 633 controls, and RCCL in 271 cases and 399 controls and their genotypes at ~185,000 single nucleotide polymorphisms. A novel fixed and random model with a circulating probability unification (FarmCPU) function, with marker-based principal components and a kinship matrix to correct for population stratification, was used. A Bonferroni correction at p<0.01 resulted in a P< 6.96 ×10-8. Six loci were identified; three for HD and three for RCCL. An associated locus at CFA28:34,369,342 for HD was described previously in the same dogs using a conventional mixed model. No loci were identified for RCCL in the previous report but the two loci for ED in the previous report did not reach genome-wide significance using the FarmCPU model. These results were supported by simulation which demonstrated that the FarmCPU held no power advantage over the linear mixed model for the ED sample but provided additional power for the HD and RCCL samples. Candidate genes for HD and RCCL are discussed. When using FarmCPU software, we recommend a resampling test, that a positive control be used to determine the optimum pseudo quantitative trait nucleotide-based covariate structure of the model, and a negative control be used consisting of permutation testing and the identical resampling test as for the non-permuted phenotypes.
髋关节发育不良（HD）、肘关节发育不良（ED）以及颅侧（前）十字韧带断裂（RCCL）是犬类最常见的复杂骨科性状，都会导致使人衰弱的骨关节炎。我们重新分析了先前报告的数据：921只犬的诺伯格角（HD的定量指标）、113例病例和633例对照的ED以及271例病例和399例对照的RCCL，以及它们在约185,000个单核苷酸多态性位点的基因型。使用了一种具有循环概率统一（FarmCPU）功能的新型固定和随机模型，该模型带有基于标记的主成分和亲属关系矩阵以校正群体分层。在p<0.01时进行Bonferroni校正，得到P<6.96×10⁻⁸。鉴定出6个位点；3个与HD相关，3个与RCCL相关。在同一批犬中，先前曾使用传统混合模型描述过一个与HD相关的位于CFA28:34,369,342的位点。先前的报告中未鉴定出与RCCL相关的位点，但先前报告中与ED相关的两个位点使用FarmCPU模型未达到全基因组显著性。模拟结果支持了这些结果，模拟表明FarmCPU在ED样本上相对于线性混合模型没有功效优势，但为HD和RCCL样本提供了额外的功效。讨论了HD和RCCL的候选基因。使用FarmCPU软件时，我们建议进行重采样测试，使用阳性对照来确定模型基于伪定量性状核苷酸的最佳协变量结构，并使用由置换检验和与未置换表型相同的重采样测试组成的阴性对照。
