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Age-Related Macular Degeneration Risk Genes, Pathways Found in Multiomics Eye Study

NEW YORK – A team led by investigators at the University of Utah, Genentech, and the State University of New York at Buffalo has used gene expression, epigenetic, and gene regulation analyses of human eye tissues to discover genes, pathways, and regulatory features relevant to age-related macular degeneration (AMD).

"Our work has revealed putative causal genes and pathways underlying genetic risk for AMD and underscores the power of a systems biology approach for elucidating mechanisms driving AMD," co-senior and co-corresponding author Margaret DeAngelis, a researcher affiliated with SUNY Buffalo and the University of Utah, and her colleagues wrote in Cell Genomics on Tuesday.

Using a combination of bulk RNA sequencing, array-based DNA methylation profiling, single-nucleus RNA-seq, and single-nucleus ATAC-seq, the researchers characterized expression, methylation, and chromatin accessibility features in normal macular retinal pigment epithelium (RPE)/choroid samples, along with samples from individuals with intermediate AMD, neovascular or "wet" AMD, or geographic atrophy (GA), a "dry" form of the disease linked to inconsistent degeneration patterns.

"To address the issue of disease heterogeneity, tissues used for bulk analyses were carefully chosen from a collection of phenotyped human ocular tissue, where the controls showed little or no signs of drusen [lipid-protein deposits], and the disease tissues were delineated by clinical staging criteria," the authors wrote, noting that they "employed single-cell genomics to complement and validate our bulk tissue approach."

The study encompasses research spanning more than a decade, DeAngelis explained in an email, and relied on samples obtained through a rapid post-mortem tissue collection program, together with detailed phenotyping to carefully delineate retina tissues and focus in on the RPE and choroid tissues where pathogenic AMD processes are suspected of starting.

"[T]his work could not have been made possible without the help of community outreach and the generous people who are willing to donate their eyes to research," she emphasized. "This is really important as there are no animal models which can fully encapsulate AMD, as the architecture of the human eye is unique and so is the biology."

Overall, the researchers generated snRNA-seq data for nearly 164,400 individual cells, bulk RNA sequence and methylation array profiles for 85 AMD or control samples, and single-cell ATAC-seq profiles for more than 125,800 individual cells from retina, RPE, and choroid tissues from half a dozen individuals with AMD and seven unaffected control individuals. Based on this, they identified chromatin accessibility peaks that overlapped with loci linked to AMD in a prior genome-wide association study, including the HTRA1 gene and the C6orf223 open-reading frame.

The team's findings also pointed to nearly two dozen loci with genome-wide significant methylation differences in the AMD cases, including late-stage disease-related methylation features. When it came to differentially expressed genes, meanwhile, the analyses highlighted more than 1,000 genes with altered activity across distinct AMD stages.

Together, the investigators explained, an integrated systems biology analysis of the available expression, methylation, gene regulation, and rare variant burden data pointed to the importance of the WNT signaling pathway regulatory genes FRZB and TLE2 in AMD pathophysiology.

"Our comprehensive molecular analysis is a major step toward understanding AMD pathogenesis and yielded a wealth of genes with relevance to disease mechanisms in human AMD," the authors reported, adding that "information presented here will be vital for developing hypotheses, for linking in vitro and in vivo models to human disease, and for providing greater precision in our therapeutic approach to AMD treatment and prevention."