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The Clinical Usefulness of a Glaucoma Polygenic Risk Score in 4 Population-Based European Ancestry Cohorts
Victor A de Vries1, Akiko Hanyuda2, Joëlle E Vergroesen1
1Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Insights
A polygenic risk score (PRS) effectively identifies individuals at high risk for primary open-angle glaucoma (POAG). Incorporating PRS into predictive models significantly enhances glaucoma detection accuracy, aiding targeted screening strategies.
Area of Science:
- Ophthalmology
- Genetics
- Epidemiology
Background:
- Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide.
- Early identification of high-risk individuals is crucial for effective management and prevention of vision loss.
- Current risk prediction models for POAG have limitations in accurately identifying at-risk populations.
Purpose of the Study:
- To utilize a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts.
- To evaluate the predictive performance of PRS in identifying POAG cases.
- To assess the potential of PRS in improving glaucoma screening strategies.
Main Methods:
- Secondary analysis of four prospective, European-ancestry population-based cohorts (Nurses' Health Study, Nurses' Health Study 2, Health Professionals Follow-up Study, and Rotterdam Study).
- Polygenic risk score weights were derived using the lassosum method on UK Biobank data, incorporating 144,020 genetic variants.
- Multivariable Cox proportional hazard models and Harrell's C statistic were used to estimate the association between PRS and POAG risk, and model concordance.
Main Results:
- Participants in the highest PRS quintile exhibited a 3.99-fold (US cohorts) and 4.89-fold (Rotterdam Study) increased relative risk for POAG compared to those with median genetic risk.
- A predictive model combining age, sex, intraocular pressure, and family history achieved a concordance of 0.75, which improved to 0.82 upon addition of the PRS.
- Individuals in the highest PRS tertile showed a larger cup-to-disc ratio and a 2.07-fold increased risk of requiring glaucoma surgery.
Conclusions:
- Integrating a polygenic risk score (PRS) into POAG predictive models significantly enhances prediction concordance from 0.75 to 0.82.
- The PRS demonstrates potential for improving the identification of individuals at high risk for POAG.
- The findings support the use of PRS in developing more cost-effective and targeted glaucoma screening strategies.
Purpose:
We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts.
Design:
Secondary analysis of 4 prospective population-based studies.
Participants:
We included four European-ancestry cohorts: the United States-based Nurses' Health Study, Nurses' Health Study 2, and the Health Professionals Follow-up Study and the Rotterdam Study (RS) in The Netherlands. The United States cohorts included female nurses and male health professionals ≤ 55 years of age. The RS included residents ≤ 45 years of age living in Rotterdam, The Netherlands.
Methods:
Polygenic risk score weights were estimated by applying the lassosum method on imputed genotype and phenotype data from the UK Biobank. This resulted in 144 020 variants, single nucleotide polymorphism and insertions or deletions, with nonzero βs that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits.
Main Outcome Measures:
The relative risk for POAG and Harrell's C statistic.
Results:
Among 1046 patients and 38 809 control participants, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08-5.18) times higher in the United States cohorts and 4.89 (2.93-8.17) times higher in the RS, compared with participants with median genetic risk (third quintile). Combining age, sex, intraocular pressure of more than 25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (95% CI, 0.73-0.75). Adding the PRS to this model improved the concordance to 0.82 (95% CI, 0.80-0.84). In a meta-analysis of all cohorts, patients in the highest tertile showed a larger cup-to-disc ratio at diagnosis, by 0.10 (95% CI, 0.06-0.14), and a 2.07-fold increased risk of requiring glaucoma surgery (95% CI, 1.19-3.60).
Conclusions:
Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.
Financial Disclosure(S):
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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