Oliver, James Andrew Clive; (2019) Pectinate ligament dysplasia and primary glaucoma in dogs: investigating prevalence and identifying genetic risk factors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Canine primary glaucoma is a painful and blinding disease associated with pathologically high intraocular pressure. The two main recognised forms are primary closed angle glaucoma (PCAG) and primary open angle glaucoma (POAG). Pectinate ligament dysplasia (PLD), an abnormality of the iridocorneal angle, is a consistent risk factor for canine PCAG. PCAG and PLD have been shown previously to be highly heritable although inheritance is considered complex. Gonioscopy was performed in > 1100 dogs of seven breeds to provide current estimates of PLD prevalence between September 2013 and March 2016. PLD was associated with age (P < 0.01) and there was inter-examiner variability in performing PLD grading (P = 0.05). These results have influenced the policy making of the United Kingdom’s canine hereditary eye disease scheme. Genome-wide association studies (GWAS) were performed to identify regions of the genome associated with PCAG in four dog breeds. Two loci (chr24:17,381,226-18,739,902 and chr37:24,747,131-24,958,250) were associated with PCAG in the Basset Hound, the former being syntenic with a region previously reported to be associated with primary glaucoma in humans. Meta-analysis of summary data from the Welsh Springer Spaniel and Dandie Dinmont Terrier GWAS analyses revealed an additional (shared) PCAG locus (chr28:18,835,904-19,358,417). Whole genome sequencing was used to interrogate PCAG loci for candidate causal variants and RNA sequencing was used to investigate candidate genes for PCAG in the Basset Hound. For POAG, a candidate gene approach was used to screen ADAMTS17 for causal mutations in three different dog breeds. POAG was shown to be an autosomal recessive trait associated with a different ADAMTS17 mutation in each breed (c.193_211del in Basset Hound, c.1552G>A in Basset Fauve de Bretagne and c.3070_3075del in Shar Pei). DNA tests have been developed to enable a reduction in the incidence of POAG in these breeds and a controlled elimination of each mutation over time.

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