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

Abstract

Importance: Rhegmatogenous retinal detachment is a potentially sight-threatening condition. The role of myopia or intraocular pressure (IOP) in retinal detachment remains unclear.

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

Design, setting, and participants: 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.

Main outcomes and measures: 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 and relevance: 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.

Figure 1.. Schematic Representation of Mendelian Randomization Analysis

Genetic variants (G) that are associated with the exposure (X, such as myopia) are used as instrumental variable. The association of genetic variants with the outcome (Y, such as retinal detachment) is only mediated through the exposure.

Figure 2.. Observational Association of Intraocular Pressure (IOP), Mean Spherical Equivalent (MSE) Refractive Error, and Retinal Detachment Risk

The x-axis is the quintiles for exposures (IOP and MSE), and the y-axis is the natural logarithm of odds ratio (log[OR]) for retinal detachment risk. In the observational logistic regression analysis, we adjusted sex and age in logistic regression models. The figure highlights that the risk of retinal detachment is approximately linearly increased with the decreasing MSE or increasing IOP. The quintiles for MSE are −22.600 to −1.910, greater than −1.910 to −0.217, greater than −0.217 to 0.486, greater than 0.486 to 1.400, and greater than 1.400 to 14.000; the quintiles for IOP are 5.080 to 13.200, greater than 13.200 to 15.000, greater than 15.000 to 16.600, greater than 16.600 to 18.700, and greater than 18.700 to 54.400. Error bars indicate 95% CIs.

Figure 3.. Association of Myopia-Increasing and Intraocular Pressure (IOP)–Increasing Risk Variants With Risk of Retinal Detachment

A, The x-axis shows 224 genetic instruments for mean spherical equivalent (MSE) refractive error and their βs (effect size estimates) with refractive error. The y-axis shows the association of the same variants with retinal detachment; the y-axis unit is the effect size of single-nucleotide variants on retinal detachment in log(odds ratio [OR]). B, The x-axis shows 99 genetic instruments for IOP, and the y-axis shows the association of them with retinal detachment. The mendelian randomization (MR) inverse-weighted (IVW), MR-Egger, simple median, and weighted median regression lines are plotted.