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Pectinate Ligament Dysplasia and Primary Glaucoma in Dogs: Investigating Prevalence And

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Pectinate Ligament Dysplasia and Primary Glaucoma in Dogs: Investigating Prevalence And Pectinate ligament dysplasia and primary glaucoma in dogs: investigating prevalence and identifying genetic risk factors James Andrew Clive Oliver A thesis submitted for the degree of Doctor of Philosophy Animal Health Trust and UCL Institute of Ophthalmology 2018 1 Declaration I, James Oliver, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. James Oliver 2 Acknowledgments Acknowledgements The inception of this project sprung from my experience in treating canine primary glaucoma. The inability to save both the sight and the eyes of affected dogs and provide hope to their owners is a source of continued frustration. My quest, therefore, was to seek help in investigating the genetics of this devastating disease because, as they say, “prevention is better than cure”. At the culmination of this frustration, I was lucky to be practising at the Animal Health Trust (AHT), where Cathryn Mellersh, my primary PhD supervisor, and her world renowned Canine Genetics Research team reside. Without Cathryn’s encouragement, support and devotion to collaborative research to enhance animal welfare, none of this research would have been possible. Thank you Cathryn. I must also thank my UCL supervisor Alison Hardcastle who has always been there in the background to offer support and encouragement. I am also indebted to Paul Foster and David Sargan for performing my first year viva and providing their constructive criticisms which helped shape the direction of the project. My heartfelt thanks extend to Sally Ricketts, Louise Burmeister, Louise Pettitt and Rebekkah Hitti at the AHT for their patience and help in instructing a simple vet in the laboratory and statistical methodology required to perform this work which was an incredibly enjoyable, although at times steep, learning curve. I also need to thank all the owners who allowed me to examine their dogs and collect DNA from them. Sincere gratitude also extends to Hannes Lohi, Markus Kuehn and Tosso Leeb who shared DNA samples which were used in the GWAS. Finally, this project would not have been possible without the financial support of Dogs Trust who funded my PhD, and of PetPlan, the European College of Veterinary Ophthalmologists, the British Association of Veterinary Ophthalmologists, the American Kennel Club and the Welsh Springer Spaniel, Flatcoated Retriever and Dandie Dinmont Terrier breed clubs and societies. 3 Abstract 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. 4 Impact statement Impact statement This PhD will deliver considerable positive effects both inside and outside academia that cumulatively will lead to the prevention of inherited forms of glaucoma in multiple populations of purebred dogs, thus positively impacting animal welfare in the short term, and also contributing to an improved understanding of the genetic aetiology of glaucoma in dogs and, potentially, other species in the longer term. Short term benefits to animal welfare have been achieved through the development of genetic tests to assay for disease-associated mutations and by the generation of current prevalence data for PLD - a risk factor for glaucoma. Thus far, the AHT has tested >400 dogs for the POAG mutations reported in this thesis which will enable breeders to eliminate POAG from their breeds while maintaining genetic diversity. Furthermore, all of the POAG mutations reported are in ADAMTS17 which emphasises this gene’s importance in canine glaucoma, make it a potential candidate for human glaucoma and, potentially, a therapeutic target of the future. The PLD prevalence data will aid breed clubs and veterinary health schemes in future surveillance of this abnormality and will be informative of the benefit of screening for PLD prior to breeding. Previous PLD prevalence data had only been published for the Flatcoated Retriever some 20 years ago and so the current data suggest that the widespread use of gonioscopy testing in this breed has been very successful in reducing PLD (and possibly glaucoma) prevalence in this breed. The PLD data have also influenced the stance of the United Kingdom’s canine hereditary eye disease scheme, with regard to recommendations regarding the necessity to perform gonioscopy in certain breeds, the frequency of gonioscopy testing and how PLD can be better graded than the existing system. In the longer term, publication of the PCAG loci identified in multiple dog breeds will provide a springboard to facilitate identification of candidate genes and variants through further work both by the AHT and by other groups. The significant findings regarding 5 Impact statement the genetics of PCAG, a complex disease, will lead to an improved understanding of the underlying genetic architecture of this disease in dogs, offering the potential for improved prevention and/or treatment strategies across species. 6 Table of contents Table of contents Declaration ....................................................................................................................... 2 Acknowledgements .......................................................................................................... 3 Abstract ............................................................................................................................ 4 Impact statement ............................................................................................................. 5 Table of contents ............................................................................................................. 7 List of figures ................................................................................................................. 12 List of tables ................................................................................................................... 15 List of abbreviations ..................................................................................................... 16 Publications and presentations .................................................................................... 18 Publications ................................................................................................................. 18 Presentations (oral) ...................................................................................................... 19 1 Introduction ................................................................................................................ 20 1.1 Anatomy and physiology of the canine aqueous humour outflow pathways ........................................................................................................... 20 1.1.1 Aqueous humour and intraocular pressure ................................................ 20 1.1.2 Aqueous humour outflow pathways .......................................................... 20 1.1.2.1 The conventional outflow pathway ......................................................... 21 1.1.2.2 The unconventional outflow pathway ..................................................... 24 1.1.2.3 Embryology of the ICA and pectinate ligament dysplasia ..................... 24 1.1.2.4 The effect of aging on the aqueous humour outflow pathways .............. 26 1.2 Classification and pathophysiology of canine primary glaucoma ................... 27 1.2.1 Gonioscopy ................................................................................................ 30 1.2.2 Primary closed angle glaucoma ................................................................. 35 1.2.3 Primary
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