Epigenetic modifiers and their interactions with genetic polymorphisms in Intraocular Pressure and glaucoma

Abstract

Purpose : Numerous genetic loci associated with intraocular pressure (IOP) and glaucoma have been discovered through genome-wide association (GWAS) studies. However, variance explained by GWAS genes is modest and the role of epigenetic systemic mechanisms or their utility as biomarkers in glaucoma is not fully known. We conducted an Epigenome association study (EWAS) for glaucoma and IOP in peripheral blood-derived DNA and also specifically assessed the interaction between GWAS SNPs and DNA methylation (DNAm) markers.

Methods : We assessed association with glaucoma and IOP and DNAm via the Illumina EPIC v1.0 DNAm BeadChip from subjects of European ancestry, recruited in the Canadian Longitudinal Study on Aging (CLSA). The primary outcome for the EWAS was glaucoma and IOP, with age and sex as covariates. Secondary, statistical interactions between Single Nucleotide Polymorphisms (SNPs) with DNAm levels observed in their vicinity (<10kbp) were modelled using as input results from previously published GWAS.

Results : After quality control, we analysed data from 783,136 DNAm probes in 1,356 individuals with available phenotypic data and no IOP-lowering medication-taking history. After multiple testing correction, three probes were significantly associated with glaucoma. The most significant (cg19830245, p=1.63x10^-11) was located within the 5’ CpG island of the overlapping PLD6 and FLCN genes with Active Promoter Chromatin Segmentation in both blood and eye tissue from EpiMap. Neither gene has been associated with glaucoma previously. PLD6 plays a crucial role in mitochondrial fusion and response to cellular stress. Additionally, after correcting for multiple testing, one significant interaction emerged from the interaction analyses, between LMO4 locus SNPs and cg06712674. No correlation was observed between these SNPs and methylation levels at that probe.

Conclusions : Epigenetic mechanisms play important roles in many diseases and conditions. Here we identify one genome-wide significant association with a DNA methylation probe near PLD6 that coordinates mitochondrial functions and its response to cellular stress, believed to be critical to the development of glaucoma. In addition, interaction of DNAm levels with SNPs may be examples of how epigenetic regulation could initiate age-related diseases, which needs to be further confirmed by independent and better powered future studies.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.