PURPOSE: We combined classical association analyses with one-sample and two-sample Mendelian randomization (MR), to comprehensively assess the causal relation among central corneal thickness (CCT), corneal hysteresis, Fuchs endothelial corneal dystrophy (FECD), and open-angle glaucoma (OAG). METHODS: We analyzed data from a large population-based cohort study (the Rotterdam Study), an FECD case-control study, and genome wide association study summary statistics. We defined OAG as reproducible visual field loss, independent of IOP. Multivariable regression was performed. One-sample MR was performed using the same regression models, with the corresponding genetic risk score (GRS) as independent variable. Two-sample MR was performed using inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode methods. RESULTS: In total, 303 participants with OAG and 10,598 controls from the Rotterdam Study were included, with 753 FECD cases from the FECD cohort. The odds ratio (OR) 95% confidence interval (CI) of OAG was 0.67 (95% CI = 0.56-0.81) per standard deviation (SD) increase in CCT (P < 0.001). However, one-sample MR showed no significant association between a CCT-GRS and OAG (P = 0.688). Two-sample MR found an OR (95% CI) of 1.23 (95% CI = 1.06-1.42) for each SD increase in the CCT instrumental variable. We observed no association between an FECD-GRS and OAG (P = 0.946). CONCLUSIONS: We found no evidence for a causal link between CCT and OAG. Nevertheless, CCT measurements are still valuable for population-based risk stratification. We found no clear relationship between FECD and OAG.

1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Epidemiology Erasmus Medical Center Rotterdam The Netherlands

Department of Ophthalmology Erasmus Medical Center Rotterdam The Netherlands

Department of Ophthalmology Radboud University Medical Center Nijmegen The Netherlands

Institute of Molecular and Clinical Ophthalmology University of Basel Basel Switzerland

Moorfields Eye Hospital London United Kingdom

NIHR Biomedical Research Centre Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology London United Kingdom

UCL Institute of Ophthalmology London United Kingdom

Zobrazit více v PubMed

Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. PubMed PMC

Wolfs RC, Klaver CC, Ramrattan RS, van Duijn CM, Hofman A, de Jong PT. Genetic risk of primary open-angle glaucoma. Population-based familial aggregation study. PubMed

Gordon MO, Beiser JA, Brandt JD, et al.. The ocular hypertension treatment study: baseline factors that predict the onset of primary open-angle glaucoma. PubMed

Jiang X, Varma R, Wu S, et al.. Baseline risk factors that predict the development of open-angle glaucoma in a population: the Los Angeles Latino Eye Study. PubMed PMC

Leske MC, Heijl A, Hyman L, et al.. Predictors of long-term progression in the early manifest glaucoma trial. PubMed

Khawaja AP, Jansonius NM. Potential for collider bias in studies examining the association of central corneal thickness with glaucoma. PubMed PMC

Buxton JN, Preston RW, Riechers R, Guilbault N. Tonography in cornea guttata. A preliminary report. PubMed

Nagarsheth M, Singh A, Schmotzer B, et al.. Relationship between Fuchs endothelial corneal dystrophy severity and glaucoma and/or ocular hypertension. PubMed PMC

Loewenstein A, Hourvitz D, Goldstein M, Ashkenazi I, Avni I, Lazar M. Association of Fuchs' corneal endothelial dystrophy with angle-closure glaucoma. PubMed

Ali ZK, Whitson JT, Mootha VV, et al.. Glaucoma in patients with corneal endothelial dystrophy. PubMed

Rice GD, Wright K, Silverstein SM. A retrospective study of the association between Fuchs' endothelial dystrophy and glaucoma. PubMed PMC

Aiello F, Gallo Afflitto G, Ceccarelli F, Cesareo M, Nucci C. Global prevalence of Fuchs endothelial corneal dystrophy (FECD) in adult population: a systematic review and meta-analysis. PubMed PMC

Skrivankova VW, Richmond RC, Woolf BAR, et al.. Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR statement. PubMed

Ikram MA, Brusselle G, Ghanbari M, et al.. Objectives, design and main findings until 2020 from the Rotterdam Study. PubMed PMC

de Vries VA, Hanyuda A, Vergroesen JE, et al.. The clinical utility of a glaucoma polygenic risk score in four population-based European-ancestry cohorts. PubMed PMC

van der Valk R, Webers CA, Schouten JS, Zeegers MP, Hendrikse F, Prins MH. Intraocular pressure-lowering effects of all commonly used glaucoma drugs: a meta-analysis of randomized clinical trials. PubMed

Cheng JW, Cheng SW, Gao LD, Lu GC, Wei RL. Intraocular pressure-lowering effects of commonly used fixed-combination drugs with timolol: a systematic review and meta-analysis. PubMed PMC

Ramdas WD, Wolfs RC, Hofman A, de Jong PT, Vingerling JR, Jansonius NM. Heidelberg retina tomograph (HRT3) in population-based epidemiology: normative values and criteria for glaucomatous optic neuropathy. PubMed

Liu S, Sadan AN, Bhattacharyya N, et al.. Genetic and demographic determinants of Fuchs endothelial corneal dystrophy risk and severity. PubMed PMC

He W, Han X, Ong JS, et al.. Association of novel loci with keratoconus susceptibility in a multitrait genome-wide association study of the UK Biobank database and Canadian longitudinal study on aging. PubMed PMC

Simcoe MJ, Khawaja AP, Hysi PG, Hammond CJ; UK Biobank Eye and Vision Consortium. Genome-wide association study of corneal biomechanical properties identifies over 200 loci providing insight into the genetic etiology of ocular diseases. PubMed PMC

Gorman BR, Francis M, Nealon CL, et al.. A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation. PubMed PMC

Kurki MI, Karjalainen J, Palta P, et al.. FinnGen provides genetic insights from a well-phenotyped isolated population. PubMed PMC

Lee H, Cashin AG, Lamb SE, et al.. A guideline for reporting mediation analyses of randomized trials and observational studies: the AGReMA statement. PubMed PMC

Burr JM, Mowatt G, Hernández R, et al.. The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation. PubMed

Eraslan N, Celikay O. Effects of topical prostaglandin therapy on corneal layers thickness in primary open-angle glaucoma patients using anterior segment optical coherence tomography. PubMed

Lesk MR, Hafez AS, Descovich D. Relationship between central corneal thickness and changes of optic nerve head topography and blood flow after intraocular pressure reduction in open-angle glaucoma and ocular hypertension. PubMed

Da Silva F, Linhares JMM, Lira M. What intrinsic factors affect the central corneal thickness? PubMed

Jackson VE, Wu Y, Bonelli R, et al.. Multi-omic spatial effects on high-resolution AI-derived retinal thickness. PubMed PMC

Zhang ZQ, Xie Z, Chen SY, Zhang X. Mitochondrial dysfunction in glaucomatous degeneration. PubMed PMC

Guo DC, Regalado ES, Gong L, et al.. LOX mutations predispose to thoracic aortic aneurysms and dissections. PubMed PMC

Mäki JM, Räsänen J, Tikkanen H, et al.. Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice. PubMed

Yengo L, Vedantam S, Marouli E, et al.. A saturated map of common genetic variants associated with human height. PubMed PMC

Regalado ES, Guo DC, Villamizar C, et al.. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. PubMed PMC

Aubart M, Gobert D, Aubart-Cohen F, et al.. Early-onset osteoarthritis, Charcot-Marie-Tooth like neuropathy, autoimmune features, multiple arterial aneurysms and dissections: an unrecognized and life threatening condition. PubMed PMC

Hu J, Gong X, Johnson ST, Corey DR, Mootha VV. The TCF4 trinucleotide repeat expansion of fuchs' endothelial corneal dystrophy: implications for the anterior segment of the eye. PubMed PMC

Sie NM, Yam GH, Soh YQ, et al.. Regenerative capacity of the corneal transition zone for endothelial cell therapy. PubMed PMC