| Title: | Nonuniform Association of Genetic Risk Scores for Intraocular Pressure |
| Journal: | JAMA Ophthalmology |
| Published: | 30 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42060295/ |
| DOI: | https://doi.org/10.1001/jamaophthalmol.2026.1022 |
Publication 17792
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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.</p>
Objective: To test the hypothesis that nonuniform behavior of genetic risk scores for IOP is associated with a specific type of genetic interaction.</p>
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.</p>
Exposures: Ninety-eight genetic variants associated with IOP.</p>
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.</p>
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.</p>
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.</p>
83 Authors
- Xi He
- Yu Huang
- Denis Plotnikov
- Louise Terry
- Jeremy A. Guggenheim
- Naomi Allen
- Tariq Aslam
- Denize Atan
- Konstantinos Balaskas
- Sarah Barman
- Jenny H. Barrett
- Paul Bishop
- Graeme Black
- Tasanee Braithwaite
- Roxana O. Carare
- Usha Chakravarthy
- Michelle Chan
- Sharon Y. L. Chua
- Alexander Day
- Alastair K. Denniston
- Parul Desai
- Bal Dhillon
- Andrew D. Dick
- Alexander Doney
- Cathy Egan
- Sarah Ennis
- Paul J. Foster
- Marcus Fruttiger
- John E. J. Gallacher
- David F. Garway-Heath
- Jane Gibson
- Chris J. Hammond
- Alison Hardcastle
- Simon P. Harding
- Ruth E. Hogg
- Pirro Hysi
- Pearse A. Keane
- Sir Peng T. Khaw
- Anthony P. Khawaja
- Gerassimos Lascaratos
- Thomas Littlejohns
- Andrew J. Lotery
- Robert Luben
- Phil Luthert
- Tom Macgillivray
- Sarah Mackie
- Savita Madhusudhan
- Bernadette Mcguinness
- Gareth Mckay
- Martin McKibbin
- Tony Moore
- James E. Morgan
- Eoin O'Sullivan
- Richard Oram
- Chris G. Owen
- Praveen J. Patel
- Euan Paterson
- Tunde Peto
- Axel Petzold
- Nikolas Pontikos
- Jugnoo S. Rahi
- Alicja R. Rudnicka
- Naveed Sattar
- Jay Self
- Panagiotis Sergouniotis
- Sobha Sivaprasad
- David Steel
- Irene Stratton
- Nicholas Strouthidis
- Cathie Sudlow
- Zihan Sun
- Robyn Tapp
- Dhanes Thomas
- Emanuele Trucco
- Adnan Tufail
- Ananth C. Viswanathan
- Veronique Vitart
- Mike Weedon
- Cathy Williams
- Katie Williams
- Jayne Woodside
- Max M. Yates
- Yalin Zheng
1 Application
| Application ID | Title |
|---|---|
| 83325 | Genetic and lifestyle risk factors for refractive error |
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