Polygenic Risk Score Identifies Individuals at Higher Risk of POAG


Individuals with a higher risk of primary open-angle glaucoma (POAG) could be identified using a polygenic risk score, recent study found.

A polygenic risk score (PRS) was able to identify individuals who had the highest risk of primary open-angle glaucoma (POAG) in a study aimed at finding the prevalence of POAG based on structural coding and self-reports. The study, published in JAMA Ophthalmology, suggests that PRS stratification may help identify those at a high risk of severe POAG to inform clinical decisions and health care resource use.

In complex diseases such as POAG, PRSs can be used to measure cumulative risk based on many disease-associated DNA variants that affect overall genetic risk. Data from the UK Biobank (UKBB) were used to determine the association between background polygenetic risk for POAG and disease diagnosis and features in a large population.

The UKK is a prospective cohort study of residents of the United Kingdom who were aged 40 to 69 years. Genotypic and phenotypic information was included for all participants, and there were 130,000 participants who had eye examinations in this dataset.

The International Classification of Diseases, Ninth Revision and Tenth Revision were used to identify individuals with POAG using diagnosis codes. Self-reported POAG (SR-POAG) was also used. Patients who had non-POAG forms of glaucoma were excluded from the study.

Fundus photographs (FP) were taken for a subset of participants. Intraocular pressure, corneal hysteresis, and corneal resistance factor that was cornea-compensated was obtained from data fields in the UKBB. Patients who used glaucoma medication were identified. Optical coherence tomography scans were also gathered from a subset of participants. The PRS for POAG was calculated with genome-wide association study (GWAS) summary statistics.

There were 407,667 participants included in the study, of which 46.2% were male and the mean (SD) age was 56.3 (8.1) years. A total of 21.5% had ocular data. Overall, 3.5% were SR-POAG cases, and 1.6% were FP-POAG cases.

The POAG PRS was used for 14,171 SR-POAG cases and 393,496 controls. Higher mean (SD) PRS was seen in individuals with SR-POAG compared with those without (0.50 [1.02] vs –0.02 [0.99]). In a model including PRS, age, sex, and ancestry, the area under receiver operating characteristic curve (AUROC) for POAG detection was 0.748.

Each POAG PRS decile had a higher prevalence of POAG. Those at the highest genetic risk of POAG in decile 10 had 5 times more prevalence of SR-POAG compared with those in decile 1 (1.3% vs 7.4%). Increased genetic risk at all ages was associated with SR-POAG prevalence, with the outcome most notable in older participants. A 1 SD increase in PRS was associated with 1.74 higher odds of SR-POAG when using a logistic regression model that adjusted for age and sex (adjusted odds ratio [aOR], 1.74; 95% CI, 1.71-1.77).

Individuals who had a higher POAG genetic risk were more likely to have FP-POAG. Among 44,411 individuals with FPs available, the AUROC for FP-POAG detection was 0.614 for PRS, and 0.683 when age, sex, and inferred ancestry were included in the model. Prevalence increased for FP-POAG from decile 1 to decile 10, and prevalence increased with genetic risk. A 1 SD increase in PRS was associated with higher odds of FP-POAG (aOR, 1.46; 95% CI, 1.36-1.58).

There were some limitations to this study. A total of 95.7% of participants were of European ancestry, and weights were derived from a GWAS with mostly European participants. UKBB participants were aged 40 to 69 years, which left out older adults who are highest risk of POAG. Inaccuracies in medication self-reporting could influence the data set. The definition of POAG used in this study also had lower specificity compared with other population-based studies. A cutoff was used to categorize FP-POAG which could have resulted in false categorization. This data set may not apply to those with normal tension glaucoma.

The researchers concluded that higher PRS was associated with more severe disease. “This study supports the increasing clinical importance of PRS risk stratification to identify individuals at higher risk of severe disease to help inform health care resource allocation and clinical decision-making,” they wrote.


Sekimitsu S, Xiang D, Lloyd Smith S, et al. Deep ocular phenotyping across primary open-angle glaucoma genetic burden. JAMA Ophthalmol. Published online August 17, 2023. doi:10.1001/jamaophthalmol.2023.3645

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