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.

青光眼（Glaucoma）是全球范围内主要的致盲性眼病，其患病率随年龄增长而升高。本研究探索了源自外周血的DNA甲基化（DNA methylation）表观遗传生物标志物与青光眼及眼内压（intraocular pressure, IOP）的关联。研究分别对加拿大老龄化纵向研究（Canadian Longitudinal Study on Aging, CLSA）中1201名欧洲裔参与者（采用Illumina EPIC v1芯片）以及TwinsUK队列843名欧洲裔参与者（采用450K芯片）的血液源性DNA甲基化（DNAm）进行了分析。针对青光眼和眼内压开展了全表观基因组关联研究（Epigenome-Wide Association Study, EWAS），校正了年龄、性别、吸烟情况及白细胞细胞类型。本研究评估了基于DNA甲基化的EpiScores对108种血浆蛋白水平的估计值与青光眼及眼内压的关联。此外，利用5种已确立的DNA甲基化“时钟”估算的生物学年龄加速情况，也被用于分析其与青光眼和眼内压的关联，并在健康与退休研究（The Health and Retirement Study, HRS；n=3453）中进行了重复验证。对单个队列中的青光眼和眼内压进行全表观基因组关联分析未发现全基因组水平的显著关联。但针对两个队列中共有的探针开展的合并全表观基因组关联分析，鉴定出2个全表观基因组显著的CpG位点：位于FRMD3启动子区的cg03498697（p=6.86×10⁻⁸）以及PALLD基因内含子区内的cg06044751（p=1.76×10⁻⁷）。EpiScore分析显示，在两个队列的荟萃分析中，存在1个与眼内压呈邦费罗尼显著关联的肿瘤坏死因子受体超家族成员1B（TNFRSF1B）蛋白水平（p=1.31×10⁻⁴）。在健康与退休研究中开展的DNA甲基化“时钟”分析发现，GrimAge时钟估算的生物学年龄加速与青光眼存在显著关联（p=0.01）。本研究鉴定出了与青光眼及眼内压相关的血液源性表观遗传生物标志物。上述研究结果有待在更大规模、更多样化的人群中进行重复验证，并通过纵向分析评估其稳定性与潜在预测价值。