advertisement
Editors Selection IGR 25-3
Risk Factors: Does corneal thickness truly raise POAG risk, or is it all bias?
Comment by Skanda Rajasundaram & Anthony Khawaja on:
126646 Central corneal thickness and the risk of primary open-angle glaucoma: a Mendelian randomisation mediation analysis, Katsimpris A; Baumeister SE; Baurecht H et al., British Journal of Ophthalmology, 2024; 109: 52-57
p>Uncertainty remains as to whether central corneal thickness (CCT) has any true biological effect on primary open-angle glaucoma (POAG) or whether it simply associates with POAG due to its spurious influence on IOP measurement. Previous observational studies adjusting for measured IOP in a multivariable model may induce a spurious association between CCT and true IOP and thus between CCT and POAG, a phenomenon known as collider bias.1 Katsimpris et al. investigate the effect of CCT on POAG liability using Mendelian randomization (MR), an approach that leverages the random allocation of genetic variants at conception to strengthen causal inference from observational data. They find genetic support for a 1.38-fold increase (95% CI 1.18 to 1.61) in the odds of developing POAG per 50um increase in CCT. Their mediation analysis estimates that 28.4% (95% CI 0 to 60%) of the effect of CCT on POAG is mediated through IOP. Thus, contrary to most prior observational studies, they conclude that thicker central corneas increase POAG liability. Numerous steps are taken to perform and report the study in line with best practice, for which the authors should be commended. Based on the present data, however, readers should be cautious in interpreting the findings.
The study considers IOP only as a potential mediator of the effect of CCT on POAG and not as a potentially pleiotropic pathway. However, genetic variants associating with CCT may also associate with IOP. Given the strong genetic association between IOP and POAG, one must be confident the MR estimate for CCT on POAG is not biased through these genetic associations with IOP and thus simply reflects a small proportion of the powerful causal effect of IOP on POAG. These genetic associations with IOP can be controlled for using Multivariable MR (MVMR). Genetically predicted IOP levels do not depend on measured IOP levels - rather, the converse is true. Thus, whilst adjusting the CCT-POAG association for measured IOP in a multivariable regression model induces collider bias, doing so in an MVMR model does not. Looking forward, MVMR could be performed using more recent2 and larger3 POAG genome-wide association study (GWAS) datasets. Pleiotropy-robust sensitivity analyses and the MR-Egger intercept test should also be reported for the CCT-IOP MR estimate because any apparent indirect effect of CCT on POAG rests on the validity of this estimate. Another challenge is that our largest POAG GWAS has substantial contributions from studies relying on self-report. In this setting, it is perhaps not surprising that a thicker CCT is associated with glaucoma, given it will lead to higher IOP measurements on average and spuriously higher glaucoma or ocular hypertension diagnosis and self-report likelihood.
Clinically, CCT remains important in accounting for corneal artefact and thus, in elucidating true IOP from measured IOP. Risk stratification using IOP combined with CCT may therefore be superior to that of measured IOP alone. In the absence of a truly causal effect on POAG liability, however, CCT alone should not be used to risk stratify the general population for glaucoma.
References
- Khawaja AP, Jansonius NM. Potential for Collider Bias in Studies Examining the Association of Central Corneal Thickness With Glaucoma. Invest Ophthalmol Vis Sci. 2022 Nov 1;63(12):3. https://doi.org/10.1167/iovs.63.12.3
- Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023;613(7944):508-518. Round 12 data can be accessed at https://www.finngen.fi/en/access_results.
- Gharahkhani P, Jorgenson E, Hysi P, et al. Genome-wide meta-analysis identifies 127 open-angle glaucoma loci with consistent effect across ancestries. Nat Commun. 2021;12(1):1258. https://doi.org/10.1038/s41467-020-20851-4
Comments
The comment section on the IGR website is restricted to WGA#One members only. Please log-in through your WGA#One account to continue.Log-in through WGA#One
