Genome-Wide Association Study Identifies a Novel Canine Glaucoma Locus

Abstract

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.

The genetic mechanisms of primary angle closure glaucoma

“…116 In addition, a GWA study of a late onset form of PACG described in a Dandie Dinmont Terrier cohort has led to the identification of a novel susceptibility locus on canine chromosome 8. 117 A recent study in a pedigree of Basset Hounds with PACG implicated variations in NEB (Nebulin), a large protein of the sarcomere that is highly expressed in the ciliary muscle of the eye. 118 These variations were also found to be associated with the disease in a study of unrelated Basset Hounds.…”

Genetics of eye disorders in the dog.

“…A similarly significant association has been reported between pectinate ligament dysplasia and adult-onset primary glaucoma in the Flatcoated retriever, for which the heritability was estimated to be approximately 0.7 [139,140]. To date no mutations have been identified that are associated with angle closure glaucoma in any breed of dog although the first glaucomaassociated locus has recently been identified in Dandie Dinmont Terriers [141].…”

Genetics of Canine Primary Glaucomas

“…1 and 2) as well as for PLL in multiple canine breeds (see Table 2). [24][25][26][27][28][29][30] As molecular technologies continue to evolve, the next-generation sequencing of the entire genome of affected animals and the search for disease mutations will become more efficient and economical.…”

“…1,3,134,139,145 The disease has been studied most thoroughly in American and English cocker spaniels, 128,129,[146][147][148][149][150][151][152] basset hound, 26,27,[127][128][129]146,[150][151][152][153][154] English and Welsh springer spaniels, 9,131 Bouvier des Flandres, 142,149 Chow Chow, 152,155 Siberian husky, 152 Great Dane, 132 flat-coated retriever, 143,156,157 Samoyed, [11][12][13] Shiba inu, 19,21,130,145 Shih Tzu, 21,145 Eurasier dog (created from Chow Chow and Samoyed), 141 Dandie Dinmont terrier, 28 and golden retriever. 158 Despite the proposed autosomal-dominant and autosomal-recessive inheritance of PACG in the Welsh springer spaniel 131 and Siberian husky, …”

“…[161][162][163] Another susceptibility locus for canine PACG was mapped to a 9.5-Mb region on canine chromosome 8 in the Dandie Dinmont terriers, but no specific disease gene could be identified by screening positional candidate genes. 28 Although individual genetic risk factors for PACG may be inherited as an autosomalrecessive trait, PACG as a whole is still considered a complex trait. For example, 88% of PACG-affected basset hounds are homozygous for the NEB risk allele; the remaining 12% are heterozygous.…”