Understanding polygenic risk testing and risk communication for glaucoma

Author: Georgina Hollitt

Hollitt, Georgina, 2024 Understanding polygenic risk testing and risk communication for glaucoma, Flinders University, College of Medicine and Public Health

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Glaucoma remains the leading cause of irreversible vision loss globally. The term describes a group of progressive optic neuropathies with retinal nerve fibre layer thinning and characteristic visual field changes. This thesis focuses on primary open angle glaucoma (POAG), as the most common subtype, which is recognised to be highly heritable. Raised intraocular pressure (IOP) is often, but not always associated with glaucoma. IOP is the only known modifiable risk factor, and IOP-lowering therapies are very effective in slowing or preventing progression. Disease progression and severity exists on a spectrum, and early diagnosis often presents a diagnostic challenge given its asymptomatic nature in the initial stage of disease. The ability to predict those who are most likely to develop glaucoma, or progress more quickly to severe disease, would vastly improve timely implementation of treatment and prevent loss of vision.

Glaucoma heritability is both Mendelian and complex. More recently, there has been significant progress in the understanding of the complex heritability of POAG, mainly through the identification of associated single-nucleotide polymorphisms from large genome wide association studies. From this, polygenic risk scores (PRS) have been developed to incorporate this knowledge into a clinically meaningful individual risk score. This tool will help to provide more objective guidance to glaucoma risk stratification in the community, especially given there are currently no established screening guidelines for glaucoma in Australia. However, important details about clinical implementation are not yet known. These gaps in knowledge include the perspectives of the community and healthcare professionals, the barriers to the uptake of the test and reporting of results, and the clinical validity of current PRS’s which have been generated in research settings. Cross-sectional questionnaire-based studies, multivariate analyses and prospective cohort studies were utilised to address these gaps.

This thesis provided original contribution to knowledge by demonstrating the first data on positive attitudes towards polygenic risk testing for POAG from key stakeholders who will be critical in the success of PRS implementation into clinical practice. This thesis further identified key contributors and barriers for individuals undertaking the test. Finally, this thesis provided novel insight into the utility of PRS in addition to family history and its association with early glaucoma treatment. The delivery of PRS testing will be an evolving journey, however this translational research will bring glaucoma PRS significantly closer to clinical implementation, and therefore, in reducing global vision loss by improving timely diagnosis and treatment.

Keywords: glaucoma, POAG, polygenic risk, PRS

Subject: Ophthalmology thesis

Thesis type: Doctor of Philosophy
Completed: 2024
School: College of Medicine and Public Health
Supervisor: Professor Jamie Craig