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. Author manuscript; available in PMC: 2026 Jan 14.
Published in final edited form as: Ophthalmol Glaucoma. 2025 Oct 21;9(2):193–201. doi: 10.1016/j.ogla.2025.10.005

A Multitrait Polygenic Risk Score for Open-Angle Glaucoma Stratifies Risk of Pigmentary Glaucoma in Pigment Dispersion Syndrome

Antonia Kolovos 1,2, Ayub Qassim 1,2, Henry N Marshall 1, Thi Thi Nguyen 1,2, Joshua Schmidt 1, Mark M Hassall 1,2, Victoria Tang 1, Giorgina Maxwell 1, John Landers 1,2, Richard Mills 1,2, Stewart Lake 1,2, Stuart L Graham 3, Angela Schulz 3, Anna Galanopoulos 4, Robert J Casson 4, Ivan Goldberg 5, Michael Coote 6, Stephen Best 7, Jed Lusthaus 5, Paul R Healey 8, Leslie Burnett 9,10, Marc Töteberg-Harms 11,12, Erin A Boese 11,12, Andrew E Pouw 11,12, Puya Gharahkhani 13,14, Todd Scheetz 11,12, Alex W Hewitt 15,16, Stuart MacGregor 13,14, Owen M Siggs 9,10, Emmanuelle Souzeau 1, John H Fingert 11,12, Jamie E Craig 1,2
PMCID: PMC12797852  NIHMSID: NIHMS2128073  PMID: 41130539

Abstract

Objective:

Pigment dispersion syndrome (PDS) is a known risk factor for glaucoma, with at least 1 in 10 patients with PDS developing glaucoma. There are no standardized clinical tools to stratify the risk of glaucoma onset or progression in the context of PDS. This study investigated whether multitrait polygenic risk scores (PRSs) built from variants collectively associated with open-angle glaucoma, intraocular pressure (IOP), and vertical cup:disc ratio (VCDR) could stratify individuals with PDS for their risk of glaucoma development.

Design:

Cross-sectional study of 2 independent PDS cohorts: the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG, n = 264), and the Glaucoma Services at the University of Iowa Carver College of Medicine (n = 203).

Participants:

Participants of European ancestry with PDS were classified as PDS-Glaucoma (n = 288), PDS-Glaucoma Suspect (n = 110), or PDS-No Glaucoma (n = 69).

Methods:

Previously published and validated PRS for open-angle glaucoma, IOP, and VCDR were expressed as a percentile or quintile of an ancestrally matched normal population. Multivariable logistic and linear regressions and survival analyses were performed.

Main Outcome Measures:

Odds of pigmentary glaucoma and odds of clinically relevant outcomes.

Results:

Participants from ANZRAG with PDS in the top quintile of an open-angle glaucoma-PRS had greater odds of glaucoma diagnosis compared with the bottom quintile (adjusted odds ratio [OR], 5.29; 95% confidence interval [CI], 1.57—21.28; P = 0.011). This observation was replicated among participants with PDS from the University of Iowa (adjusted OR, 4.07; 95% CI, 1.24—13.85; P = 0.021). Among those with PDS-Glaucoma across both cohorts combined, participants in the top quintile of glaucoma-PRS compared with the bottom quintile were diagnosed 8 years earlier (95% CI, 5.17—10.41; P < 0.001), recorded a maximum IOP 8 mmHg higher (95% CI, 2.89—11.95; P = 0.001), were at greater risk of escalation to incisional surgery (adjusted OR, 1.37; 95% CI, 1.03—1.87; P = 0.038), and were at greater risk of additional incisional surgeries to the same eye (adjusted OR, 1.27; 95% CI, 1.08—1.52; P = 0.006). A PRS for IOP also differentiated pigmentary glaucoma status; a PRS for VCDR did not.

Conclusions:

A multitrait PRS for open-angle glaucoma stratifies risk of glaucoma onset and disease severity among individuals with PDS.

Keywords: Genetics, Glaucoma, Pigmentary glaucoma, Pigment dispersion syndrome, Polygenic risk

Pigment dispersion syndrome (PDS) is an established risk factor for glaucoma.1 Identifying individuals with PDS who are at greater risk of pigmentary glaucoma is an important aspect of care. The clinical course of PDS is variable, ranging from no glaucoma to severe glaucoma.2 The lifetime conversion risk of PDS to pigmentary glaucoma is estimated to be between 35% and 50%.2—6 Although pigmentary glaucoma constitutes 1% to 1.5% of all glaucomas, it is the leading cause of glaucoma in young adults.7 Risk factors for glaucoma conversion and severity remain incompletely understood.8 ,9 Elevated intraocular pressure (IOP) is appreciated to be a significant risk factor; myopia is associated with PDS development, although its relationship with pigmentary glaucoma is yet to be elucidated.

Pigment dispersion syndrome and pigmentary glaucoma are common complex disorders without any large causative factors.10—12 The heritability of pigmentary glaucoma due to common genetic variants has been estimated at 45%,13 ,14 supporting the potential value for genetic profiling in this disease. However, only a single genome-wide association study of PDS/pigmentary glaucoma has been conducted, identifying 2 loci associated with the disease and explaining 6.9% of heritable pigmentary glaucoma.15

This study investigated pigmentary glaucoma risk stratification by a previously validated multitrait primary open-angle glaucoma (POAG) polygenic risk score (PRS),16 herein referred to as glaucoma-PRS. A PRS reflects the cumulative risk of common genetic variants associated with a disease or trait. This glaucoma-PRS has previously stratified the risk of glaucoma diagnosis and severity within European POAG populations.16—19 Additionally, we have examined stratification by an IOP-PRS20,21 and a vertical cup:disc ratio (VCDR)-PRS,16 which encapsulate common genetic variants associated with each of these traits. We hypothesized that the development of glaucomatous optic neuropathy in individuals with pigment dispersion shares common genetic drivers with POAG.

Methods

Study Design and Aims

This study examined whether a glaucoma-PRS stratified the risk of pigmentary glaucoma among participants with PDS. We performed a cross-sectional multicohort study, which primarily examined whether 3 PRSs (multitrait for open-angle glaucoma, IOP, and VCDR) stratified participants with PDS by risk of glaucoma development. Next, we examined whether the PRS could stratify the risk of the following clinical parameters: age of pigmentary glaucoma diagnosis, highest-recorded IOP, escalation to incisional surgery, and multiple incisional surgeries.

Participants

Participants with an ophthalmologist diagnosis of PDS (with or without glaucoma) and available genotypes were drawn from 2 independent cohorts. The first cohort was drawn from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG)22 (total PDS n = 264), a national, multicenter genetic registry. Pigment dispersion syndrome with or without glaucoma is a recruitment category in ANZRAG. The second cohort was derived from the Glaucoma Service, Department of Ophthalmology at the University of Iowa Carver College of Medicine (total PDS n = 203). Participants were recruited consecutively because they presented for review between January 2000 and March 2024. Each participant contributed 1 eye with PDS to the study. In bilateral cases, the worst eye with PDS was used to capture the severity of this asymmetric disease. The worst eye was defined by the lower mean deviation (MD) on perimetry testing for the ANZRAG cohort and the highest-recorded IOP for the University of Iowa cohort.

Pigment dispersion syndrome was clinically diagnosed by referring ophthalmologists, where a participant was observed to have Krukenberg spindles, radial mid-peripheral iris transillumination defects, and hyperpigmentation of the trabecular meshwork (all 3 required in the same eye). Participants with equivocal examination findings were not recruited. Pigment dispersion syndrome was diagnosed the same way in both cohorts by board-certified glaucoma specialists, not by chart review. Pigmentary glaucoma status was assigned as either (1) pigmentary glaucoma (PDS-Glaucoma); (2) PDS with glaucoma suspect or ocular hypertension (PDS-Suspect); or (3) PDS with an otherwise normal glaucoma examination and ancillary testing (PDS-None). Pigment dispersion syndrome—glaucoma was defined as those with an ophthalmologist-graded glaucomatous field defect on reliable perimetric testing with corresponding optic disc changes.22 Pigment dispersion syndrome-Suspect was defined as those with either disc morphology suspicious for glaucoma23,24 or the highest-recorded IOP >21 mmHg but without a glaucomatous field defect.25 Pigment dispersion syndrome-None was defined as individuals who did not meet either criterion. High-tension glaucoma was defined as the highest-recorded IOP measured as >21 mmHg. Advanced glaucoma status was assigned for the ANZRAG cohort, defined as a MD on Humphrey visual field 24–2 SITA-Standard testing worse than −15 decibels (dB) in the worst affected eye, or 2 of the 4 points within the 10 ° central fixation depressed below P < 0.5% on the pattern deviation plot.22

Clinical data of the highest-recorded IOP, incisional surgery, age of diagnosis, and severity of field loss were collected on recruitment to each cohort and updated where available from clinical follow-up appointments. Intraocular pressure was measured by Goldmann applanation tonometry in both cohorts. Incisional surgery included trabeculectomy and tube shunt surgery (Baerveldt, Molteno, Ahmed). Age of diagnosis for participants with PDS-Glaucoma was determined by the age of pigmentary glaucoma diagnosis. Although the data are cross-sectional, referring ophthalmologists update participants’ clinical status to ensure PDS-Suspect/None who manifest glaucoma are accurately relabeled as PDS-Glaucoma. The most recent reliable Humphrey Visual Field 24–2 was collected for the ANZRAG cohort, and the MD was recorded in dB for the worst eye. The primary outcome was examined within each cohort separately. The secondary outcomes were examined with the cohorts combined to increase statistical power. Visual field severity was only available for examination within the ANZRAG cohort.

Ancestry was determined using genetic principal components. Only participants of European genetic ancestry were included in the analysis because the PRS used in this study were developed and validated within European cohorts. Two participants from the ANZRAG cohort, and 6 from the University of Iowa cohort had non-European genetic ancestry were thus excluded. Closely related individuals were defined as pi-hat value >0.2 based on identity by descent from autosomal markers; the index participant was included, and other(s) excluded. Participants diagnosed with another secondary glaucoma were excluded to eliminate potential confounding.

This study adhered to the tenets of the revised Declaration of Helsinki and had ethics approval from either the Southern Adelaide Clinical Human Research Ethics Committee or the Institutional Review Board at the University of Iowa. All participants provided written informed consent.

Calculation of PRSs

DNA extracted from peripheral blood was genotyped on either Omni1M, OmniExpress, HumanCoreExome, or Infinium Global Screening Arrays (Illumina). Samples were batched by array platform, and after standard quality control, single-nucleotide polymorphisms (SNPs) genotypes were imputed and phased against the Haplotype Reference Consortium 1.1 reference panel using the Michigan Imputation Server.26 ,27

Polygenic risk score was calculated using PLINK2 software (version PLINK v2.00a6).28 The glaucoma-PRS was calculated for each individual using a previously described multitrait analysis of genome-wide association studies for open-angle glaucoma.16 The glaucoma-PRS contained 2673 SNPs associated with an open-angle glaucoma diagnosis, as well as IOP and VCDR endophenotypes.16 Separate PRS for IOP and VCDR were also calculated using only SNPs associated with these traits.16,20 A myopia-PRS29 (Polygenic Score Catalog ID PGS002211) was used as a covariate in regression to account for the genetic correlation between PDS and myopia in lieu of complete data for clinical markers such as refraction or axial length, which was not consistently recorded in our data sets. The myopia-PRS included >825 000 SNPs identified by case-control genome-wide association study of a myopia diagnosis from n >390 000 individuals from the UK Biobank.29

Each PRS was standardized to reference data from the 1000 Genomes Project.30 Only European participants, as determined by genetic principal component analysis, from the 1000 Genomes Project were included, thus creating an independent ancestrally matched normative population (i.e., EUR). Polygenic risk score was expressed as a population-derived percentile when comparing distributions between groups, or as a population-derived quintile in regression models for ease of clinical interpretation. No participant used in the discovery or validation of the PRS was included in the following statistical analyses.

Statistical Analysis

All statistical analyses were performed in ‘R’ (v4.3.0, R Core Team). Nonparametric data were examined with Wilcoxon signedrank test (2 groups) and Kruskal—Wallis (multiple groups). Generalized multivariable logistic and linear regression models were adjusted for age at examination, genetically-inferred sex, and myopia-PRS. Survival analyses (survminer function, “R”) were used to analyze time to pigmentary glaucoma diagnosis. The P value for statistical significance was set at 0.05.

Results

The baseline characteristics of the ANZRAG and University of Iowa PDS cohorts are outlined in Table 1. The majority of participants were male in both cohorts (66.6% and 66.5% respectively). The median age of examination was 55.2 (interquartile range [IQR], 43.2—62.3) and 57.0 (IQR, 47.1—65.2) years, respectively. When both cohorts were combined, those with PDS-Glaucoma comprised the majority (n = 288), followed by PDS-Suspect (n = 110), and PDS-None (n = 69). Among those with PDS-Glaucoma, when combining both cohorts, half (49.6%) had advanced disease, and the majority (90.0%) had documented high-tension glaucoma; the remaining cases (n = 28) did not have a pretreatment IOP measurement available for classification.

Table 1.

Baseline Characteristics of the Australian and New Zealand Registry of Advanced Glaucoma Cohort and the University of Iowa Cohort

PDS-None PDS-Suspect PDS-Glaucoma P
Australian and New Zealand registry cohort
 N 39 90 135
 Male N (%) 19 (48.7) 64 (71.1) 93 (68.9) 0.034
 Age of examination, yrs Median (IQR) 47.2 (20.8) 53.4 (21.5) 57.2 (17.7) 0.19
 Myopia-PRS, percentile Median (IQR) 70.7 (47.0) 60.1 (49.3) 62.9 (50.1) 0.25
 Highest-recorded IOP Median (IQR) 17.8 (3.2) 27.3 (7.4) 30.2 (10.9) <0.001
 Age of pigmentary glaucoma diagnosis, median (IQR) NA NA 46 (17.2) NA
 Advanced pigmentary glaucoma status, N (%) 0 (0) 0 (0) 67 (49.6) NA
 At least 1 incisional surgery N (%) 0 (0) 0 (0) 45 (33.3) NA
 Additional incisional surgery to the same eye, N (%) 0 (0) 0 (0) 38 (21.8) NA
University of Iowa, clinic cohort
 N 30 20 153
 Male n (%) 17 (56.7) 14 (70.0) 104 (68.0) 0.45
 Age of examination, yrs Median (IQR) 57.5 (18.8) 55.0 (16.0) 58.0 (18.0) 0.83
 Myopia-PRS, percentile Median (IQR) 65.6 (36.2) 38.3 (34.1) 63.0 (49.9) 0.48
 Highest-recorded IOP Median (IQR) 20.5 (11.4) 29.4 (5.2) 33.0 (11.8) <0.001
 Age of pigmentary glaucoma diagnosis, median (IQR) NA NA 48 (18.8) NA
 Advanced pigmentary glaucoma status, N (%) Not available for this cohort
 At least 1 incisional surgery N (%) 0 (0) 0 (0) 129 (84.3) NA
 Additional incisional surgery to the same eye, N (%) 0 (0) 0 (0) 54 (35.3) NA
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IOP = intraocular pressure; IQR = interquartile range; NA = not applicable; PDS = pigment dispersion syndrome; PRS = polygenic risk score.

P values derived from χ2 test for frequency count, and the Kruskal—Wallis test for nonparametric data.

The distribution of the genetic risk by common variants for glaucoma, IOP, and VCDR among the entire PDS cohort is seen in Figure 1 (values presented in Table S1, available at www.ophthalmologyglaucoma.org). The median glaucoma-PRS was statistically higher between the PDS-Glaucoma and PDS-Suspect, as well as between the PDS-Glaucoma and PDS-None. The median IOP-PRS was statistically higher between the PDS-Glaucoma and the PDS-None group. These trends show that those with pigmentary glaucoma harbor a greater burden of common risk variants for these traits compared with PDS without glaucoma.

Figure 1.

Figure 1.

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Genetic distribution of variants associated with open-angle glaucoma, intraocular pressure (IOP), and vertical cup:disc ratio (VCDR) across the pigment dispersion syndrome (PDS) phenotypes. Box and whisker plot of the glaucoma-polygenic risk score (PRS), IOP-PRS, and VCDR-PRS distribution across the combined PDS cohort (n = 467). The PRS is expressed as a percentile of an ancestrally matched normative population. Blue represents PDS-None, green represents PDS-Suspect, and red represents PDS-Glaucoma. The solid black line indicates the median PRS value for the group, the box indicates the interquartile range, and the whiskers indicate the spread of data. P values are shown above the gray bars, calculated by Wilcoxon sign-rank test.

The primary analysis examined the glaucoma-PRS risk stratification of pigmentary glaucoma. The distribution of participants across quintiles is shown in Table S2 (available at www.ophthalmologyglaucoma.org). Within the ANZRAG cohort, participants in the top quintile were at fivefold risk (adjusted odds ratio [OR], 5.29; 95% confidence interval [CI], 1.57—21.28; P = 0.011) of developing pigmentary glaucoma compared with those in the bottom quintile, after adjusting for age at examination, sex, and myopia-PRS. Age was a significant predictor, whereas sex and myopia-PRS were not (age: adjusted OR, 1.05; 95% CI, 1.03—1.07; P < 0.001; sex: adjusted OR, 1.38; 95% CI, 0.76—2.51; P = 0.30; myopia-PRS: adjusted OR, 1.00; 95% CI, 0.99—1.01; P = 0.85). This observation was consistent within the University of Iowa cohort. Pigment dispersion syndrome participants within the University of Iowa cohort in the top quintile exhibited a fourfold risk (adjusted OR, 4.07; 95% CI, 1.24—13.85; P = 0.021) of developing glaucoma compared with those in the bottom quintile, after adjusting for age at examination, sex, and myopia-PRS. Similarly, age was a significant predictor (age: adjusted OR, 1.04; 95% CI, 1.01—10.7; P = 0.004; sex: adjusted OR, 1.25; 95% CI, 0.60—2.56; P = 0.53; myopia-PRS: adjusted OR, 1.00; 95% CI, 0.99—1.02; P = 0.53). When combining both cohorts, participants with PDS in the top quintile were at fivefold (adjusted OR, 5.42; 95% CI, 2.23—13.98; P < 0.001) risk of developing glaucoma compared with those in the bottom quintile, after adjusting for age at examination, sex, and myopia-PRS. Age was significant (age: adjusted OR, 1.05; 95% CI, 1.03—10.7; P < 0.001; sex: adjusted OR, 1.35; 95% CI, 0.87—2.10; P = 0.18; myopia-PRS: adjusted OR, 1.00; 95% CI, 0.99—1.01; P = 0.90). Myopia-PRS was not a significant predictor in these models, suggesting that myopia is likely a consistent risk factor for PDS development but not a strong risk factor for pigmentary glaucoma development. The area under the receiver operating characteristic curve of this multivariable model was 0.71 (95% CI, 0.65—0.75), demonstrating a moderate ability of the PRS to discriminate between PDS-Glaucoma and PDS-None.

In a secondary analysis, we examined glaucoma endpoints of relevance in both cohorts combined. Participants with PDS-Glaucoma in the top quintile glaucoma-PRS were diagnosed with pigmentary glaucoma approximately 8 years earlier (adjusted estimate, 7.81 years; 95% CI, 5.17—10.41; P < 0.001) compared with the bottom quintile, after adjusting for age at examination, sex, and myopia-PRS. The median survival, defined as manifest pigmentary glaucoma, was 10 years earlier in those with the highest quintile of glaucoma-PRS at 58 years of age compared with the remainder of the cohort (quintiles, 1—4) (Fig 2). This indicates participants harboring a greater burden of glaucoma risk variants, as captured by a higher glaucoma-PRS, were at higher risk of earlier glaucoma manifestation.

Figure 2.

Figure 2.

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Survival analysis of pigmentary glaucoma cases among the pigment dispersion syndrome (PDS) cohort stratified by genetic risk. Cumulative proportion of pigmentary glaucoma cases within the combined PDS cohort by age of pigmentary glaucoma diagnosis and stratified by glaucoma-polygenic risk score (PRS) quintile (n = 467). Glaucoma status is determined at the most recent examination date, and cases are censored after the most recent examination. The graph ends at 70 years due to insufficient observations beyond this age bracket to draw reliable conclusions. The PRS is expressed as a quintile of an ancestrally matched normative population. Red represents those with a PRS in the top population quintile (PRS ≥80.0%), while orange represents the remainder of the cohort (PRS <80%). The median survival, defined as manifest pigmentary glaucoma, was 10 years earlier in those with the highest quintile of glaucoma-PRS at 58 years of age compared with the remainder of the cohort.

Finally, we tested whether the glaucoma-PRS could stratify other clinical outcomes. Among all PDS cases, participants in the top quintile of glaucoma-PRS had the highest-recorded IOP 8 mmHg higher than the bottom quintile (adjusted estimate, 7.42; 95% CI, 2.89—11.95; P = 0.001) after adjusting for age, sex, and myopia-PRS. The median highest-recorded IOP of the top glaucoma-PRS quintile was 33 mmHg (IQR, 25—40) compared with 22 mmHg (IQR, 20—32) of the bottom quintile. The median MD of the top glaucoma-PRS quintile was −7.68 dB lower than the bottom quintile (median, −8.78 dB [IQR, −4.1 to −14.0] compared with −1.1 dB [IQR, 1.0 to −2.1]; P = 0.02). Among those with PDS-Glaucoma, the glaucoma-PRS differentiated risk of escalation to incisional surgery, with risk increasing by 37% (adjusted OR, 1.37; 95% CI, 1.03—1.87; P = 0.038) for each increasing glaucoma-PRS quintile in a logistic regression adjusting for age at examination and sex. Fifty-seven percent (n = 65/114) of the top quintile underwent at least 1 incisional surgery compared with 14.8% (n = 4/27) in the bottom quintile (P < 0.001). The glaucoma-PRS also stratified risk of a second incisional surgery to the same eye, with risk increasing by 27% (adjusted OR, 1.27; 95% CI, 1.08—1.52; P = 0.006) with each increasing glaucoma-PRS quintile. Forty percent (n = 45/114) of the top glaucoma-PRS quintile underwent a second incisional surgery compared with 0/27 in the bottom quintile (P = 0.025). Key results are summarized in Table S3 (available at www.ophthalmologyglaucoma.org). This suggested participants with a higher glaucoma-PRS harbored genetic variants associated with poorer disease outcomes and the need for surgical intervention.

Discussion

Because pigmentary glaucoma may follow an aggressive disease course and disproportionately affects younger individuals, identifying patients at greater risk of poor outcomes is critical. This study assessed the clinical validity of a glaucoma-PRS to stratify glaucoma risk within a PDS cohort. Among those with PDS, a glaucoma-PRS stratified risk of glaucoma development, age at glaucoma diagnosis, highest-recorded IOP, and escalation to incisional surgery. Reported conversion rates from PDS to pigmentary glaucoma vary by cohort (e.g., ancestry, registry vs. screening population) and duration of follow-up, but range from 10% to 50%.3,6 Utilization of PRS alongside clinical features could facilitate personalized glaucoma risk assessment, with clinical implications for the monitoring and management of patients with PDS.

Predictors of conversion from PDS to pigmentary glaucoma remain incompletely understood. Elevated IOP at initial examination is considered the strongest associated predictor.3 ,4 There is conflicting evidence on whether age, sex, diopters of myopia, and family history are associated with conversion to pigmentary glaucoma.2 ,31—37 Subjective clinical metrics, including severity of iris transillumination, active pigment liberation, or Sampaolesi line, are weak predictors for glaucoma conversion or severity3,6,35 and vulnerable to interobserver and intraobserver variability.38 A glaucoma-PRS is an objective tool with direct clinical translation that offers glaucoma risk stratification among individuals with PDS.

The glaucoma-PRS was predictive of initial incisional surgery and additional incisional surgery in patients with pigmentary glaucoma. This is in keeping with our previous reports that the glaucoma-PRS is predictive of trabeculectomy within POAG cohorts.19 Within this present study, although the reason for additional incisional surgery was not collected, this group had a statistically higher maximum IOP, suggesting that the reason may be due to uncontrolled IOP, or requiring a lower IOP because of intrinsic disease severity or progression (which could plausibly be captured by the glaucoma-PRS). Alternatively, bleb fibrosis (which would not be captured by a glaucoma-PRS) could be the reason, but this would then render the participant again susceptible to their underlying glaucoma-PRS pathology.

The results of this study, and another similar analysis of pseudoexfoliative glaucoma,39 support a shared pathophysiology between the open-angle glaucomas. The glaucoma-PRS consists of common genetic variants associated with open-angle glaucoma (most of which is POAG, but may also include both pseudoexfoliative and pigmentary glaucoma cases), IOP, and VCDR. Given this glaucoma-PRS can stratify outcomes within the PDS cohort, it suggests that at least a portion of the genetic variants captured within the glaucoma-PRS are also variants driving pigmentary glaucoma. We observed a difference in the IOP-PRS between groups, but no difference in the VCDR-PRS, indicating that there is a difference in the burden of common risk variants associated with IOP across the disease spectrum. This is consistent with the literature that pigmentary glaucoma is a pressure-driven disease, and IOP is a risk factor for conversion.3,4

Previous studies have demonstrated the clinical validity of an open-angle glaucoma-PRS among POAG cohorts, stratifying individuals at high and low risk for developing POAG.16,40—43 The glaucoma-PRS used in this study is a multitrait PRS, leveraging the genetic correlation of endophenotypic traits to glaucoma and improving the stratification power of this tool. The results of this study demonstrate the clinical validity of this glaucoma-PRS to stratify risk of pigmentary glaucoma and clinically relevant outcomes among individuals with PDS. This finding has not been previously reported, although we have recently reported similar findings in multiple cohorts affected with pseudoexfoliation syndrome,39 shedding new light on a long-standing clinical conundrum.

Our study is one of the largest genetic studies of PDS and pigmentary glaucoma, of particular significance given the low prevalence of this condition. It is the first to examine the clinical validity of an open-angle glaucoma-PRS within pigmentary glaucoma. A limitation of this study was the unavailability of myopic status or refraction for a portion of the cohort; we addressed this by applying a genetic correction with a myopia-PRS. Although the currently available myopia-PRS may not capture the full heritability of myopia, it captures genetic variants associated with both myopia and PDS to correct for this interaction.15,29,44 The exclusion of non-European ancestry participants from the analysis limits the application of these findings to other populations. Although the ANZRAG and University of Iowa did not exclude recruitment based on self-reported ethnicity, there were insufficient numbers of non-European patients (n = 8) to examine this concept within ancestry-specific cohorts. The smaller sample size of the PDS-None phenotype is a limitation, reflective of ascertainment bias because recruitment was conducted from a glaucoma registry and service. Although not statistically different, the PDS-None group had a nominally younger age at examination than the other phenotypes, meaning that they may still manifest glaucoma in their lifetime. Clinical status was updated for each participant, thus ensuring accurate phenotyping to address this.

In summary, using 2 separate cohorts, we demonstrated that a glaucoma-PRS holds clinical validity in identifying PDS patients at risk of pigmentary glaucoma. This novel clinical tool was able to stratify risk of glaucoma, age of diagnosis, highest-recorded IOP, and escalation to incisional surgery. A glaucoma-PRS could be applied in the clinic to improve the management algorithms for PDS patients.

Supplementary Material

Supplementary Table 3: Summary of key results
Supplementary Table 1: Distribution of the three PRS types expressed as a percentile of a normative population, across the two cohorts separately and combined.
Supplementary Table 2: Distribution of participants with PDS across the Glaucoma-PRS quintiles

Disclosures:

All authors have completed and submitted the ICMJE disclosures form.

The authors made the following disclosures: M.M.H.: Equity owner ― Seonix Pty Ltd.

R.J.C.: Equity owner ― Seonix Pty Ltd.

S.M.: Director ― Seonix Pty Ltd (a company commercializing polygenic risk scores); Equity owner ― Seonix Pty Ltd; Patent ― Application for the use of genetic risk scores in predicting glaucoma risk (AU201890220601).

O.M.S.: Director ― Seonix Pty Ltd (a company commercializing polygenic risk scores); Equity owner ― Seonix Pty Ltd.

J.E.C.: Equity owner ― Seonix Pty Ltd; Patent ― Application for the use of genetic risk scores in predicting glaucoma risk (AU201890220601).

The other authors have no proprietary or commercial interest in any materials discussed in this article.

J.E.C. and S.M. acknowledge Program (grant no.: 1150144) funding from the Australian National Health and Medical Research Council (NHMRC). J.E.C., S.M., E.S., and P.G. acknowledge Fellowship and Investigator grant funding from the Australian NHMRC. P.G. acknowledges support from the BrightFocus Foundation. O.M.S. acknowledges support from the Snow Medical Research Foundation. J.H.F. and T.S. acknowledge support from the grant no.: NIH RO1EY035266 and grant no.: EY035679 and Research to Prevent Blindness. The sponsor or funding organization had no role in the design or conduct of this research.

The Article Publishing Charge (APC) for this article was paid by Flinders University.

Abbreviations and Acronyms:

ANZRAG

Australian and New Zealand Registry of Advanced Glaucoma

CI

confidence interval

dB

decibels

IOP

intraocular pressure

IQR

interquartile range

MD

mean deviation

OR

odds ratio

PDS

pigment dispersion syndrome

POAG

primary open-angle glaucoma

PRS

polygenic risk score

SNP

single-nucleotide polymorphism

VCDR

vertical cup:disc ratio

Footnotes

HUMAN SUBJECTS: This study adhered to the tenets of the revised Declaration of Helsinki and had ethics approval from either the Southern Adelaide Clinical Human Research Ethics Committee (SAC HREC) or the Institutional Review Board at the University of Iowa. All participants provided written informed consent.

No animal subjects were used in this study.

Supplemental material available at www.ophthalmologyglaucoma.org.

Data Availability

The participants of this study did not give written consent for their data to be shared publicly, supporting data is not available.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table 3: Summary of key results
NIHMS2128073-supplement-Supplementary_Table_3__Summary_of_key_results.pdf (129.5KB, pdf)
Supplementary Table 1: Distribution of the three PRS types expressed as a percentile of a normative population, across the two cohorts separately and combined.
NIHMS2128073-supplement-Supplementary_Table_1__Distribution_of_the_three_PRS_types_expressed_as_a_percentile_of_a_normative_population__across_the_two_cohorts_separately_and_combined_.pdf (142.6KB, pdf)
Supplementary Table 2: Distribution of participants with PDS across the Glaucoma-PRS quintiles
NIHMS2128073-supplement-Supplementary_Table_2__Distribution_of_participants_with_PDS_across_the_Glaucoma-PRS_quintiles.pdf (138.1KB, pdf)

Data Availability Statement

The participants of this study did not give written consent for their data to be shared publicly, supporting data is not available.

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