Risk stratification and clinical utility of polygenic risk scores in ophthalmology

Combining genetic and clinical data into an informative risk prediction profile has been an important ambition of personalized medicine. Single-nucleotide polymorphisms are commonly found throughout the genome and account for the majority of interindividual genetic variation. To date, genome-wide association studies have led to the discovery of thousands of disease-associated loci, including across dozens of ophthalmic diseases and traits. However, compared with the clinical utility of identifying rare Mendelian variants, the translation of these results to clinical practice has so far been limited because such variants are found commonly in the population, and individually account for a very small risk. Recently, combining large numbers of these genetic variants into polygenic risk scores (PRS) has shown clinically meaningful risk prediction across several common diseases. PRS have the potential to translate the discovery of common risk variants into individualized disease risk prediction, prognostication, and may enable targeted treatments. In this context, we review the clinical utility of PRS in three common, genetically complex ophthalmic conditions: primary open angle glaucoma, age-related macular degeneration, and myopia. Translational Relevance: Common genetic variants can be used to effectively stratify the risk of disease development and progression and may be used to guide screening, triaging, monitoring, or treatment thresholds.Ayub Qassim, Emmanuelle Souzeau, Georgie Hollitt, Mark M. Hassall, Owen M. Siggs, and Jamie E. Crai

Normal-tension glaucoma is associated with cognitive impairment

Published Online First 29 March 2021Background/aims: Recent research suggests an association between normal-tension glaucoma (NTG) and dementia. This study investigated whether cognitive impairment is more strongly associated with NTG than high tension glaucoma (HTG) using cognitive screening within an Australiasian Glaucoma Disease Registry. Methods: The authors completed a case–control cross sectional cognitive screening involving 290 age-matched and sex-matched NTG participants and HTG controls aged ≥65 randomly sampled from the Australian and New Zealand Registry of Advanced Glaucoma. Cognitive screening was performed using the Telephone Version of the Montreal Cognitive Assessment (T-MoCA). The T-MoCA omits points requiring visual interpretation, accounting for confounding factors related to vision loss in visually impaired participants. Cognitive impairment was defined by a T-MoCA score of <11/22. Cognition was compared between NTG and HTG participants using predetermined thresholds and absolute screening scores. Results: A total of 290 participants completed cognitive assessment. There were no differences in NTG (n=144) and HTG (n=146) cohort demographics or ocular parameters at baseline. Cognitive impairment was more prevalent in the NTG cohort than the HTG cohort (OR=2.2; 95% CI 1.1 to 6.7, p=0.030). Though a linear trend was also observed between lower absolute T-MoCA scores in the NTG cohort when compared with the HTG cohort, this association was not statistically significant (p=0.108). Conclusion: This study demonstrated an association between NTG status and poor cognition, supporting the hypothesis that there exists a disease association and shared pathoaetiological features between NTG and dementia.Sean Mullany, Lewis Xiao, Ayub Qassim, Henry Marshall, Puya Gharahkhani, Stuart MacGregor, Mark M Hassall, Owen M Siggs, Emmanuelle Souzeau, Jamie E Crai

A glaucoma polygenic risk score strongly associated with disease prediction and treatment intensity

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.Jamie E Craig; Ayub Qassim; Xikun Han; Mark Hassall; Robert James Casson; Stuart L Graham; David A Mackey; Colin Willoughby; Kathryn P Burdon; John Landers; Emmanuelle Souzeau; Janey L Wiggs; Alex W Hewitt; Stuart MacGrego

Greater physical activity is associated with neuroretinal thinning in glaucomatous and normative cohorts

Ella Claire Berry, Henry Marshall, Sean Mullany, Santiago Diaz Torres, Joshua Schmidt, Daniel Thomson, Mark Hassall, Stewart R Lake, Richard A Mills, John Landers, Stuart MacGregor, Robert Casson, Owen Siggs, Jamie E Crai

Diagnostic yield of candidate genes in an Australian corneal dystrophy cohort

First published: 19 August 2022Corneal dystrophies describe a clinically and genetically heterogeneous group of inherited disorders. The International Classification of Corneal Dystrophies (IC3D) lists 22 types of corneal dystrophy, 17 of which have been demonstrated to result from pathogenic variants in 19 identified genes. In this study, we investigated the diagnostic yield of genetic testing in a well-characterised cohort of 58 individuals from 44 families with different types of corneal dystrophy. Individuals diagnosed solely with Fuchs endothelial corneal dystrophy were excluded. Clinical details were obtained from the treating ophthalmologist. Participants and their family members were tested using a gene candidate and exome sequencing approach. We identified a likely molecular diagnosis in 70.5% families (31/44). The detection rate was significantly higher among probands with a family history of corneal dystrophy (15/16, 93.8%) than those without (16/28, 57.1%, p = .015), and among those who had undergone corneal graft surgery (9/9, 100.0%) compared to those who had not (22/35, 62.9%, p = .041). We identified eight novel variants in five genes and identified five families with syndromes associated with corneal dystrophies. Our findings highlight the genetic heterogeneity of corneal dystrophies and the clinical utility of genetic testing in reaching an accurate clinical diagnosis.Emmanuelle Souzeau, Owen M. Siggs, Sean Mullany, Joshua M. Schmidt, Mark M. Hassall, Andrew Dubowsky, Angela Chappell, James Breen, Haae Bae, Jillian Nicholl, Johanna Hadler, Lisa S. Kearns, Sandra E. Staffieri, Alex W. Hewitt, David A. Mackey, Aanchal Gupta, Kathryn P. Burdon, Sonja Klebe, Jamie E. Craig, Richard A. Mill

Using Icare HOME tonometry for follow-up of patients with open-angle glaucoma before and after selective laser trabeculoplasty

IMPORTANCE: Monitoring the results of selective laser trabeculoplasty (SLT) on intraocular pressure (IOP) using a home rebound tonometry. BACKGROUND: To evaluate the role of Icare® HOME tonometry in open-angle glaucoma patients being treated with SLT. DESIGN: A clinic-based prospective case study. PARTICIPANTS: 14 eyes from 14 patients diagnosed with primary open-angle glaucoma were recruited. METHODS: The trabecular meshwork of each eye was treated 360° with a frequency doubled Q-switched Nd:YAG laser. IOP was measured four times a day for a week before and after SLT. On the day of SLT, the patients were required to measure the IOP in the evening to record any IOP spikes. MAIN OUTCOME MEASURES: The use of Icare® HOME in following up patients post laser trabeculoplasty without the need for clinic attendance. RESULTS: Icare® HOME recorded a significant reduction of 5.12mmHg in the mean IOP post SLT (95% confidence interval [CI] 3.75-6.50mmHg, P <0.001). The maximum IOP was also reduced by 6.14mmHg (95% CI 3.07-9.21, P <0.001) with no IOP spikes recorded post SLT. There was a reduction in IOP fluctuation post SLT by 1.07mmHg (95% CI 0.24-1.89mmHg, P = 0.021). No adverse effects for using the Icare® HOME were reported by the study participants. CONCLUSION AND RELEVANCE: This methodology could be highly useful for facilitating safe follow-up of patients residing in remote and rural areas, thus reducing healthcare cost with better information on IOP. This article is protected by copyright. All rights reserved.Mona S. Awadalla, Ayub Qassim, Mark Hassall, Thi T. Nguyen, John Landers, Jamie E. Crai

Long-term survival rates of patients undergoing vitrectomy for diabetic retinopathy in an Australian population: a population-based audit - Response

Ebony Liu, Jose Estevez, Georgia Kaidonis, Mark Hassall, John Landers, Stewart Lake, Jamie E. Crai