Risks of retinal detachment for myopes: a genetic analysis

Paper title: Association of Myopia and Intraocular Pressure With Retinal Detachment in European Descent Participants of the UK Biobank Cohort: A Mendelian Randomization Study

Authors: Han, Xikun (1,2); Ong, Jue-Sheng (1); An, Jiyuan (1); Craig, Jamie E (3); Gharahkhani, Puya (1); Hewitt, Alex W (4,5); MacGregor, Stuart (1)

1. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
2. School of Medicine, University of Queensland, Brisbane, Australia
3. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Australia
4. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
5. Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia

Date: Jun 2020

Reference: Han X, Ong JS, An J, Craig JE, Gharahkhani P, Hewitt AW, MacGregor S. Association of Myopia and Intraocular Pressure With Retinal Detachment in European Descent Participants of the UK Biobank Cohort: A Mendelian Randomization Study. JAMA Ophthalmol. 2020 Jun 1;138(6):671-678

[Link to open access paper]

Rhegmatogenous retinal detachment (RDD) can occur if there is a break or tear in the neurosensory retina, causing it to separate from the underlying retinal pigment epithelium.^1,2 This can be a sight-threatening condition which reportedly has an approximate prevalence of 1% (or between 6.3-17.9 per 100,000 individuals per year), depending on country and ethnicity.³  Epidemiological and observational studies have found associations with age and cataract surgery but also myopia, where there is a 3-fold increased risk for myopes.^3-6  Raised Intra-ocular pressure (IOP) has also been found following retinal surgery but no direct link to RDD has yet been discovered.^7,8 However, these associations can also be confounding risk factors and without the strength of a randomised clinical trial results, the role of myopia in RDD incidence is unclear.

This study used observational analysis and Mendelian Randomisation to examine genetic data of the UK Biobank cohort (n = 405,692) for causal associations between myopia (n = 95,827) and IOP (n = 101, 939) and the risk of retinal detachment. Mean values for mean spherical equivalent refractive error and for corneal-compensated IOPs were calculated. Myopia was classed as being between -0.75 to -5.00D with high myopia -5.00D or stronger. The mean age of the cohort was 56.87yrs, the MES was -0.31D, the mean corneal-compensated IOP was 16.05mmHg and 1% (n = 4253) had retinal detachment. Myopia was found to give a 2.5-fold increased risk of cataracts.

The risk of retinal detachment was found to increase linearly with increased myopia and IOP:

• For each 6.00D higher myopia, the risk of retinal detachment increased 7.2-fold.
• For each per-unit mmHg increase in IOP, the risk of retinal detachment increased by 8%.

Genetic analyses showed 2 novel retinal detachment genes: COL22A1 and FAT3.

This study found support for a genetic link between higher myopia and IOP with retinal detachment and that myopia increases the risk of cataracts. These results highlight the importance of reducing myopia progression in children. If high myopia can be avoided then the risks of retinal detachment, either as a direct consequence or as a result of cataract surgery, are lower.

Limitations of this study include:

• Only using data from a European cohort, meaning the results may not apply to other racial or ethnic groups.
• The association of high myopia with retinal detachment may be partly confounded by cataract surgery being a risk factor itself.
• An assumption that a linear relationship exists between myopia and IOP and RRD, although it may be the case that they are independent risk factors.

Further studies are needed to confirm the genetic associations found for retinal detachment and how best to mitigate the risks.

Title: Association of Myopia and Intraocular Pressure With Retinal Detachment in European Descent Participants of the UK Biobank Cohort: A Mendelian Randomization Study

Authors: Xikun Han, Jue-Sheng Ong, Jiyuan An, Jamie E Craig, Puya Gharahkhani , Alex W Hewitt, Stuart MacGregor

Purpose: To determine if myopia or IOP is associated with retinal detachment risk using genetic data.

Methods: Observational analyses and 2-sample mendelian randomization were used to evaluate the associations between myopia, IOP, and retinal detachment risk in European descent participants from the UK Biobank (UKBB) cohort (n = 405 692). For retinal detachment, a genome-wide association study on 4257 cases and 39 181 controls in the UKBB was conducted. Genetic variants associated with mean spherical equivalent (MSE) refractive error (n = 95 827) and IOP (n = 101 939) were derived using independent participants from the retinal detachment genome-wide association study. Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from February 2019 to March 2020.

The odds ratio (OR) of retinal detachment caused by per-unit increases in MSE refractive error (in diopters [D]) and IOP (in mm Hg).

Results: Of the 405 692 participants in the UKBB cohort, the mean (SD) age was 56.87 (7.96) years, the mean (SD) MSE was -0.31 (2.65) D, the mean (SD) corneal-compensated IOP was 16.05 (3.49) mm Hg, and 4253 participants (1.0%) had retinal detachment. Genetic analyses of the 4257 cases and 39 181 controls identified 2 novel retinal detachment genes: COL22A1 (lead single-nucleotide variant rs11992725; P = 4.8 × 10-10) and FAT3 (lead single-nucleotide variant rs10765568; P = 1.2 × 10-15). Genetically assessed MSE refractive error was negatively associated with retinal detachment (per-unit [D] increase in MSE refractive error: OR, 0.72; 95% CI, 0.69-0.76; P = 3.8 × 10-44). For each 6-D decrease in MSE refractive error (representing the move of refractive error from emmetropia to high myopia), retinal detachment risk increased 7.2-fold (95% CI, 5.19-9.27). For per-unit (mm Hg) genetically assessed increase in IOP, the risk of retinal detachment increased by 8% (OR, 1.08; 95% CI, 1.03-1.14; P = .001).

Conclusions: This study provides genetic support for the assertion that myopia and IOP are associated with the risk of retinal detachment and that myopia prevention efforts may help prevent retinal detachment.

[Link to open access paper]