Identification of blood-derived DNA methylation biomarkers of glaucoma and intraocular pressure measurements in three European ancestry cohorts including the Canadian longitudinal study on aging

Glaucoma is a major cause of blindness globally and its prevalence rises with age. This study explored systemic blood-derived DNA methylation epigenetic biomarkers for association with glaucoma and intraocular pressure (IOP). Blood-derived DNA methylation (DNAm) was analyzed in 1,201 European participants from the Canadian Longitudinal Study on Aging (CLSA; Illumina EPIC v1 array) and 843 European participants from TwinsUK (450k array). An Epigenome-Wide Association Study (EWAS) for glaucoma and IOP was conducted, adjusting for age, sex, tobacco smoking, and leukocyte cell types. DNAm-based EpiScores estimates for 108 plasma protein levels were evaluated for associations with glaucoma and IOP. Additionally, ‘biological’ age acceleration, estimated using five established DNAm ‘clocks,’ was assessed for glaucoma and IOP and replicated in The Health and Retirement Study (HRS; <i>n</i> = 3,453). EWAS analyses of glaucoma and IOP in individual cohorts did not identify genome-wide significant associations. However, a combined EWAS for overlapping probes in both cohorts identified two epigenome-wide significant CpGs: cg03498697 in the <i>FRMD3</i> promoter (<i>p</i> = 6.86x10⁻⁸) and cg06044751 intronically within <i>PALLD</i> (<i>p</i> = 1.76x10⁻⁷). EpiScore analysis revealed one IOP Bonferroni-significant association with TNFRSF1B levels in the meta-analysis of both cohorts (<i>p</i> = 1.31x10⁻⁴). DNAm ‘clock’ analysis in the HRS identified a GrimAge-positive age acceleration associated with glaucoma (<i>p</i> = 0.01). This study identified significant epigenetic blood-derived biomarkers that are associated with glaucoma and IOP. These findings warrant replication in larger and more diverse populations as well as via longitudinal analysis to assess their robustness and potential predictive power.