Ricketts Sally L, Ahonen Saija, Pettitt Louise, Freyer Jamie, Ellis Stuart, Jenkins Christopher A, Kaukonen Maria, Boursnell Mike, Schofield Ellen, Forman Oliver P, Lohi Hannes, Mellersh Cathryn S
Canine Genetics Centre, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
PLoS One. 2025 Apr 4;20(4):e0320878. doi: 10.1371/journal.pone.0320878. eCollection 2025.
Primary hereditary cataract affects many purebred domestic dog breeds and is a major cause of visual impairment in dogs. Cataracts are common in Northern breeds such as the Siberian Husky, Alaskan Malamute and Samoyed, but their aetiology is currently unknown. Only two genetic loci are known to be causally related to primary hereditary cataracts in the dog. To search for genetic loci associated with cataracts in Northern breeds, we used a genome-wide association study approach in three breeds-Siberian Husky, Alaskan Malamute and Samoyed. Cases were defined as dogs with bilateral posterior polar subcapsular cataracts and controls were at least four years of age with no evidence of cataracts or other ocular abnormality. We found a genome-wide statistical association for cataracts in the Siberian Husky on canine chromosome 18 (P-value: 1.1 x 10 - 7), which was independently replicated in a second larger case-control set (P-value 9.8 x 10 - 29). The Samoyed breed also showed evidence for association in the same genomic region (P-value: 2.4 x 10 - 5). We subsequently used targeted resequencing of the associated region (6.5 Mb) in ten Siberian Huskies and whole genome sequencing of a Husky, Malamute, Samoyed and Norwegian Buhund case to conduct fine-mapping and screen for candidate causal variants. These analyses identified a region of linkage disequilibrium in the four breeds containing common variants in the carnitine palmitoyltransferase 1A (CPT1A) gene that are strongly associated with bilateral posterior polar subcapsular cataracts in the Siberian Husky, Samoyed, Icelandic Sheepdog and Norwegian Buhund and we demonstrate that CPT1A is expressed in the dog lens and retina through RNAseq. Our findings represent a novel locus for cataracts in dogs. However, further work is needed to elucidate the pathophysiology underlying the association between CPT1A and cataracts in Northern breeds.
原发性遗传性白内障影响许多纯种家养犬品种，是犬类视力障碍的主要原因。白内障在北方品种如西伯利亚哈士奇、阿拉斯加马拉穆特和萨摩耶中很常见，但其病因目前尚不清楚。目前已知只有两个基因位点与犬类原发性遗传性白内障有因果关系。为了寻找与北方品种白内障相关的基因位点，我们在三个品种——西伯利亚哈士奇、阿拉斯加马拉穆特和萨摩耶中采用了全基因组关联研究方法。病例定义为患有双侧后极性囊下白内障的犬，对照为至少四岁且无白内障或其他眼部异常证据的犬。我们在犬第18号染色体上发现了西伯利亚哈士奇白内障的全基因组统计学关联（P值：1.1×10−7），这在第二个更大的病例对照组中得到了独立重复验证（P值9.8×10−29）。萨摩耶品种在同一基因组区域也显示出关联证据（P值：2.4×10−5）。随后，我们对十只西伯利亚哈士奇相关区域（6.5 Mb）进行了靶向重测序，并对一只哈士奇、一只马拉穆特、一只萨摩耶以及一只挪威布洪德犬病例进行了全基因组测序，以进行精细定位并筛选候选因果变异。这些分析在四个品种中确定了一个连锁不平衡区域，该区域包含肉碱棕榈酰转移酶1A（CPT1A）基因中的常见变异，这些变异与西伯利亚哈士奇、萨摩耶、冰岛牧羊犬和挪威布洪德犬的双侧后极性囊下白内障密切相关，并且我们通过RNA测序证明CPT1A在犬晶状体和视网膜中表达。我们的发现代表了犬类白内障的一个新位点。然而，需要进一步的研究来阐明CPT1A与北方品种白内障之间关联的病理生理学机制。
