Epigenetic disease mechanisms associated with age-related macular degeneration

Abstract

Purpose : Approximately half of the susceptibility to age-related macular degeneration (AMD) is determined by genetic predisposition. The remaining risk largely originates from environmental factors, with the most important contribution from aging. Advanced age and environment can modify genetic risk for AMD through tissue-specific epigenetic changes, especially DNA methylation. Our goal is to identify differentially methylated loci (DML) in the retina of patients with AMD to understand how local epigenetic changes are involved in disease pathogenesis.

Methods : We applied whole genome bisulfite sequencing (WGBS) to study the changes in DNA methylation in postmortem human retina at single base resolution. We selected retina samples of 6 donors with late AMD and 6 age and gender-matched control individuals. DML between cases and controls were identified using R-package DSS. We performed GO enrichment analysis and CentriMo utility in MEME suite along with Transfac was used for transcription factor binding site enrichment analysis.

Results : We identified 743 DML (false discovery rate < 0.05); of which, 342 were within or near (+- 10 kb) retina-expressed genes. GO analysis showed enrichment for neuronal processes and cell adhesion. Furthermore, DML were enriched for transcription factor binding site motifs associated with known AMD-associated pathways. Comparison with a parallel WGBS project on aging-associated DNA methylation changes in mouse rod photoreceptors revealed a 10% overlap in genes, implicating specific aging mechanisms involved in AMD pathogenesis. Evaluation of epigenetic age provided preliminary evidence of accelerated aging in AMD retina compared to healthy retina. We have initiated a validation study, selecting retinas from 96 donors (40 controls, 28 intermediate AMD, 28 late AMD) for epigenome-wide analysis using MethylationEPIC BeadChip, to further explore the role of DNA methylation and its association with gene expression and genetic variation.

Conclusions : Our studies provide strong evidence supporting a significant role of DNA methylation changes in AMD pathogenesis and indicate a direct association with specific age-related processes. Epigenetic studies of the retina should help elucidate the interplay between genetics and environment in AMD and identify tissue-specific disease mechanisms to improve therapeutic targeting.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.