Genome-wide association study identifies a novel canine glaucoma locus.
Genome-wide association study identifies a novel canine glaucoma locus.
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DOI：
10.1371/journal.pone.0070903
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Lohi H
中科院分区：
文献类型：
--
作者：
Ahonen SJ;Pietilä E;Mellersh CS;Tiira K;Hansen L;Johnson GS;Lohi H
青光眼是一种视神经病变，是导致失明的主要原因之一。其遗传形式分为原发性闭角型青光眼（PCAG）、原发性开角型青光眼（POAG）和原发性先天性青光眼（PCG）。虽然许多基因座已被定位在人类，只有少数基因已被确定与青光眼的发展和疾病的遗传基础仍然知之甚少。青光眼在许多犬种中也有描述，包括丹迪丁蒙特梗（DDT），它是一种迟发性（>7年）疾病。我们设计了临床和遗传学研究，以更好地定义DDT中青光眼的临床特征，并确定遗传原因。临床诊断基于受影响犬的眼科检查和另外研究的18只未受影响的DDT。我们从400多个DTT中收集了DNA，并在23名受影响者和23名对照者的队列中进行了全基因组关联研究，随后进行了精细定位，复制研究和候选基因测序。临床研究表明，包括虹膜角膜角异常和梳状韧带发育不良在内的眼部异常在该品种中很常见（分别为50%和72%），并且该疾病类似于人类PCAG。遗传学研究在犬8号染色体上发现了一个新的9.5 Mb基因座，包括1.6 Mb的最佳相关区域（p = 1.63×10−10，纯合性OR=32）。 在五个候选基因的突变筛选没有发现任何致病变异。这项研究表明，虽然眼部异常是常见的滴滴涕，青光眼的遗传风险是由一个新的基因座CFA8。犬基因座与人类染色体14 q上的一个区域共线性，该区域含有几个与POAG和PCG相关的基因座。我们的研究揭示了犬青光眼的一个新位点，正在进行的分子研究可能有助于了解该疾病的遗传病因。
Glaucoma is an optic neuropathy and one of the leading causes of blindness. Its hereditary forms are classified into primary closed-angle (PCAG), primary open-angle (POAG) and primary congenital glaucoma (PCG). Although many loci have been mapped in human, only a few genes have been identified that are associated with the development of glaucoma and the genetic basis of the disease remains poorly understood. Glaucoma has also been described in many dog breeds, including Dandie Dinmont Terriers (DDT) in which it is a late-onset (>7 years) disease. We designed clinical and genetic studies to better define the clinical features of glaucoma in the DDT and to identify the genetic cause. Clinical diagnosis was based on ophthalmic examinations of the affected dogs and 18 additionally investigated unaffected DDTs. We collected DNA from over 400 DTTs and a genome wide association study was performed in a cohort of 23 affected and 23 controls, followed by a fine mapping, a replication study and candidate gene sequencing. The clinical study suggested that ocular abnormalities including abnormal iridocorneal angles and pectinate ligament dysplasia are common (50% and 72%, respectively) in the breed and the disease resembles human PCAG. The genetic study identified a novel 9.5 Mb locus on canine chromosome 8 including the 1.6 Mb best associated region (p = 1.63×10−10, OR = 32 for homozygosity). Mutation screening in five candidate genes did not reveal any causative variants. This study indicates that although ocular abnormalities are common in DDTs, the genetic risk for glaucoma is conferred by a novel locus on CFA8. The canine locus shares synteny to a region in human chromosome 14q, which harbors several loci associated with POAG and PCG. Our study reveals a new locus for canine glaucoma and ongoing molecular studies will likely help to understand the genetic etiology of the disease.
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