Nonuniform Association of Genetic Risk Scores for Intraocular Pressure

Importance: Elevated intraocular pressure (IOP) is a risk factor for primary open-angle glaucoma, and genetic risk scores hold promise as a tool for screening for ocular hypertension. However, genetic risk scores for IOP have a nonuniform association across the range of IOP, which reduces their accuracy. Objective: To test the hypothesis that nonuniform behavior of genetic risk scores for IOP is associated with a specific type of genetic interaction. Design, Setting, and Participants: Cross-sectional, post hoc genetic association studies were performed using linear and quantile regression in a sample of UK Biobank participants. Data were analyzed from January to September 2025. Exposures: Ninety-eight genetic variants associated with IOP. Main Outcomes and Measures: Tests were carried out for 98 genetic variants associated with IOP (P < 5.0 ×10-8) to examine (1) dominant or recessive genetic effects, (2) genotype × genotype interactions, (3) genotype × age interactions, and (4) genotype × sex interactions. Results: A total of 98 235 participants (mean [SD] age, 58.1 [7.9] years; 52 168 female [53.1%]) were included in this analysis. More variants exhibited genotype × age interactions than expected by chance (14 of the 98 variants associated with IOP had at least nominal evidence of an interaction with age; P = 3.76 ×10-4). For 12 of these 14 variants, age increased rather than decreased the magnitude of the IOP vs genotype association. However, integrating age interactions into the genetic risk score construction process did not yield improved accuracy (incremental noninteraction model, R2 = 4.05; 95% CI, 3.82-4.31 and interaction model, R2 = 4.04; 95% CI, 3.80-4.27). There was little support for other types of genetic interaction. Conclusions and Relevance: In the current work, findings show minimal evidence that nonadditive allelic effects, genotype × genotype interactions, and genotype × sex interactions contributed to the nonuniform association of genetic variants with IOP across quantiles of IOP. Although a genetic risk score for IOP was more accurate in older vs younger individuals, efforts to account for genotype × age interactions in genetic risk score construction did not improve accuracy. These findings suggest other factors, such as gene-environment interactions, contribute to the nonuniform relationship of genetic variants with IOP.

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Journal
JAMA Ophthalmology
Published
2026-04-30
DOI
https://doi.org/10.1001/jamaophthalmol.2026.1022
Primary Topic
Glaucoma and retinal disorders
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article
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article

Nonuniform Association of Genetic Risk Scores for Intraocular Pressure

Pearse A. Keane, AA Khawaja, M McKibbin, Marcus Fruttiger et al.
JAMA Ophthalmology
Glaucoma and retinal disorders
article

Nonuniform Association of Genetic Risk Scores for Intraocular Pressure

Pearse A. Keane, AA Khawaja, M McKibbin, Marcus Fruttiger, Konstantinos Balaskas, Adnan Tufail, Tünde Pető, Gerassimos Lascaratos, Usha Chakravarthy, Parul Desai, Denis Plotnikov, David F. Garway‐Heath, Andrew D. Dick, Jeremy A. Guggenheim, Denize Atan, NJ Allen, Graeme Black, Jay Self, Euan Paterson, Cathy Egan, S K Khaw, Jugnoo Sangeeta Rahi, Emanuele Trucco, Bernadette McGuinness, Xi He, Louise Terry, Tariq Aslam, Paul J. Foster, John Gallacher, Axel Petzold, A J Lotery, Sobha Sivaprasad, Praveen J. Patel, Véronique Vitart, Simon Harding, Alastair Keith Denniston, Alicja R. Rudnicka, Dhanes Thomas, Yalin Zheng, Cathie Sudlow, Savita Madhusudhan, Tasanee Braithwaite, S C Barman, Nikolas Pontikos, Sharon Chua, D Steel, Zihan Sun, Prof. Alison Hardcastle, Irene Stratton, Roxana O. Carare, Prof. James E. Morgan, Y Q Huang, S R Ennis, Ananth C. Viswanathan, Sarah Mackie, Michelle Chan, Alexander Doney, Mike Weedon, Bal Dhillon, Prof. Jenny H. Barrett, Prof. Chris J. Hammond, Jayne Woodside, Ruth E. Hogg, Gareth; id_orcid 0000-0001-8197-6280 McKay, Robyn Tapp, Robert Luben, N Sattar, Panagiotis Sergouniotis, Max M. Yates, Nicholas Strouthidis, Chris G. Owen, Cathy Williams, Alexander Day, Tom Macgillivray, Paul Bishop, Katie Williams, Eoin O’Sullivan, Jane Gibson, Tony Moore, Richard Oram, Phil Luthert, Thomas Littlejohns, Pirro Hysi
article en

Abstract

Importance: Elevated intraocular pressure (IOP) is a risk factor for primary open-angle glaucoma, and genetic risk scores hold promise as a tool for screening for ocular hypertension. However, genetic risk scores for IOP have a nonuniform association across the range of IOP, which reduces their accuracy. Objective: To test the hypothesis that nonuniform behavior of genetic risk scores for IOP is associated with a specific type of genetic interaction. Design, Setting, and Participants: Cross-sectional, post hoc genetic association studies were performed using linear and quantile regression in a sample of UK Biobank participants. Data were analyzed from January to September 2025. Exposures: Ninety-eight genetic variants associated with IOP. Main Outcomes and Measures: Tests were carried out for 98 genetic variants associated with IOP (P < 5.0 ×10-8) to examine (1) dominant or recessive genetic effects, (2) genotype × genotype interactions, (3) genotype × age interactions, and (4) genotype × sex interactions. Results: A total of 98 235 participants (mean [SD] age, 58.1 [7.9] years; 52 168 female [53.1%]) were included in this analysis. More variants exhibited genotype × age interactions than expected by chance (14 of the 98 variants associated with IOP had at least nominal evidence of an interaction with age; P = 3.76 ×10-4). For 12 of these 14 variants, age increased rather than decreased the magnitude of the IOP vs genotype association. However, integrating age interactions into the genetic risk score construction process did not yield improved accuracy (incremental noninteraction model, R2 = 4.05; 95% CI, 3.82-4.31 and interaction model, R2 = 4.04; 95% CI, 3.80-4.27). There was little support for other types of genetic interaction. Conclusions and Relevance: In the current work, findings show minimal evidence that nonadditive allelic effects, genotype × genotype interactions, and genotype × sex interactions contributed to the nonuniform association of genetic variants with IOP across quantiles of IOP. Although a genetic risk score for IOP was more accurate in older vs younger individuals, efforts to account for genotype × age interactions in genetic risk score construction did not improve accuracy. These findings suggest other factors, such as gene-environment interactions, contribute to the nonuniform relationship of genetic variants with IOP.

JAMA Ophthalmology
University of Liverpool (GB), University of Dundee (GB), Kazan State Medical University (RU), Ninewells Hospital (GB), UK Biobank (GB), Guangdong Academy of Medical Sciences (CN), Genomics (United Kingdom) (GB), Guangdong Provincial People's Hospital (CN), Southern Medical University (CN), Cardiff University (GB)
Good health and well-being
Openalex Percentile: Top 8%
Glaucoma and retinal disorders
DOIOpen Access PDFOpenAlex
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