Glaucoma Genetic Risk Scores in the Million Veteran Program

Waksmunski, Andrea R.; Kinzy, Tyler G.; Cruz, Lauren A.; Nealon, Cari L.; Halladay, Christopher; Simpson, Piana; Canania, Rachael L.; Anthony, Scott A.; Roncone, David P.; Rogers, Lea Sawicki; Leber, Jenna N.; Dougherty, Jacquelyn M.; Greenberg, Paul B.; Sullivan, Jack; Wu, Wen‐Chih; Iyengar, Sudha K.; Crawford, Dana C.; Peachey, Neal S.; Bailey, Jessica N. Cooke

doi:10.1016/j.ophtha.2022.06.012

Cited by 11 publications

(9 citation statements)

References 81 publications

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“…While the increase in absolute risk appeared lower than the 6-fold to 45-fold increases seen in other studies, it is important to note that our study includes only patients with OHTN with healthy optic nerves at baseline but increased risk of conversion compared with those with normal IOP. 20,43,44 Furthermore, low-risk patients may have undiscovered protective variants not captured by our PRS. Analysis of collinearity between PRS and other baseline covariates only showed a significant association with mean (SD) VCDR, with a modest increase from 0.36 (0.20) to 0.43 (0.20) from the lowest to highest PRS tertile (Table ).…”

Section: Discussionmentioning

confidence: 99%

“…The decreased risk attributable to PRS tertile in later phases of OHTS was most likely due to increasing contributions of age or cumulative environmental burden. While the increase in absolute risk appeared lower than the 6-fold to 45-fold increases seen in other studies, it is important to note that our study includes only patients with OHTN with healthy optic nerves at baseline but increased risk of conversion compared with those with normal IOP . Furthermore, low-risk patients may have undiscovered protective variants not captured by our PRS.…”

Section: Discussionmentioning

confidence: 99%

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Polygenic Risk Scores for Glaucoma Onset in the Ocular Hypertension Treatment Study

Singh,

Zhao,

Elze

et al. 2024

JAMA Ophthalmol

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ImportancePrimary open-angle glaucoma (POAG) is a highly heritable disease, with 127 identified risk loci to date. Polygenic risk score (PRS) may provide a clinically useful measure of aggregate genetic burden and improve patient risk stratification.ObjectiveTo assess whether a PRS improves prediction of POAG onset in patients with ocular hypertension.Design, Setting, and ParticipantsThis was a post hoc analysis of the Ocular Hypertension Treatment Study. Data were collected from 22 US sites with a mean (SD) follow-up of 14.0 (6.9) years. A total of 1636 participants were followed up from February 1994 to December 2008; 1077 participants were enrolled in an ancillary genetics study, of which 1009 met criteria for this analysis. PRS was calculated using summary statistics from the largest cross-ancestry POAG meta-analysis, with weights trained using 8 813 496 variants from 449 186 cross-ancestry participants in the UK Biobank. Data were analyzed from July 2022 to December 2023.ExposuresFrom February 1994 to June 2002, participants were randomized to either topical intraocular pressure–lowering medication or close observation. After June 2002, both groups received medication.Main Outcomes and MeasuresOutcome measures were hazard ratios for POAG onset. Concordance index and time-dependent areas under the receiver operating characteristic curve were used to compare the predictive performance of multivariable Cox proportional hazards models.ResultsOf 1009 included participants, 562 (55.7%) were female, and the mean (SD) age was 55.9 (9.3) years. The mean (SD) PRS was significantly higher for 350 POAG converters (0.24 [0.95]) compared with 659 nonconverters (−0.12 [1.00]) (P &lt; .001). POAG risk increased 1.36% (95% CI, 1.08-1.64) with each higher PRS decile, with conversion ranging from 9.52% (95% CI, 7.09-11.95) in the lowest PRS decile to 21.81% (95% CI, 19.37-24.25) in the highest decile. Comparison of low-risk and high-risk PRS tertiles showed a 2.0-fold increase in 20-year POAG risk for participants of European and African ancestries. In the subgroup randomized to delayed treatment, each increase in PRS decile was associated with a 0.52-year (95% CI, 0.01-1.03) decrease in age at diagnosis (P = .047). No significant linear association between PRS and age at POAG diagnosis was present in the early treatment group. Prediction models significantly improved with the addition of PRS as a covariate (C index = 0.77) compared with the Ocular Hypertension Treatment Study baseline model (C index = 0.75) (P &lt; .001). Each 1-SD higher PRS conferred a mean hazard ratio of 1.25 (95% CI, 1.13-1.44) for POAG onset.Conclusions and RelevanceHigher PRS was associated with increased risk for POAG in patients with ocular hypertension. The inclusion of a PRS improved the prediction of POAG onset.Trial RegistrationClinicalTrials.gov Identifier: NCT00000125

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Polygenic Risk Scores for Glaucoma Onset in the Ocular Hypertension Treatment Study

Singh,

Zhao,

Elze

et al. 2024

JAMA Ophthalmol

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“…Given the variability in allele frequency, linkage disequilibrium (LD), and underlying genetic architecture between ancestral populations, limited cross-ancestry variation is to be expected [29]. Others have consistently shown that the failure of known POAG loci to replicate at genome-wide significance in POAG GWAS of African ancestry populations [27,28,[30][31][32][33] results, in part because of reduced statistical power due to admixture. Population diversity in Africa raises similar challenges to genetic analysis [34].…”

Section: Representation Of Populations Of African Descent In Primary ...mentioning

confidence: 99%

“…Figure 1 shows that allele frequencies for many of the 127 most recently identified POAG loci differ between European-descent (CEU) and African (YRI) ancestral populations as represented by 1000 Genomes (Phase 3) data [37]. We recently showed that a GRS built on this most current set of POAG risk variants consistently underperforms in African Americans [33]. Expanding diverse representation in PRS development and testing represents an opportunity for increased understanding of POAG genetic risk and facilitate a path for precision medicine for those at risk for POAG.…”

Section: Representation Of Populations Of African Descent In Primary ...mentioning

confidence: 99%

“…In European-descent samples, a higher burden of genetic risk captured by PRS is associated with POAG age at diagnosis and diseaserelevant clinical parameters [15,16]. However, in African-descent groups the predictive We recently showed that a GRS built on this most current set of POAG risk variants consistently underperforms in African Americans [33]. Expanding diverse representation in PRS development and testing represents an opportunity for increased understanding of POAG genetic risk and facilitate a path for precision medicine for those at risk for POAG.…”

Section: Clinical Applicability Of Genetic Data In Poag Risk Stratifi...mentioning

confidence: 99%

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Diversity in Polygenic Risk of Primary Open-Angle Glaucoma

Bailey

Funk

Cruz

et al. 2022

Genes

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Glaucoma is the leading cause of irreversible blindness worldwide. Primary open-angle glaucoma (POAG), the most common glaucoma subtype, is more prevalent and severe in individuals of African ancestry. Unfortunately, this ancestral group has been historically under-represented among genetic studies of POAG. Moreover, both genetic and polygenic risk scores (GRS, PRS) that are typically based on genetic data from European-descent populations are not transferable to individuals without a majority of European ancestry. Given the aspirations of leveraging genetic information for precision medicine, GRS and PRS demonstrate clinical potential but fall short, in part due to the lack of diversity in these studies. Prioritizing diversity in the discovery of risk variants will improve the performance and utility of GRS and PRS-derived risk estimation for disease stratification, which could bring about earlier POAG intervention and treatment for a disease that often goes undetected until significant damage has occurred.

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Power of inclusion: Enhancing polygenic prediction with admixed individuals

Tanigawa,

Kellis

2023

The American Journal of Human Genetics

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Glaucoma Genetic Risk Scores in the Million Veteran Program

Cited by 11 publications

References 81 publications

Polygenic Risk Scores for Glaucoma Onset in the Ocular Hypertension Treatment Study

Polygenic Risk Scores for Glaucoma Onset in the Ocular Hypertension Treatment Study

Diversity in Polygenic Risk of Primary Open-Angle Glaucoma

Power of inclusion: Enhancing polygenic prediction with admixed individuals

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