Multiomics eye study identifies genes with age-related macular degeneration risks

A team of researchers used gene expression, epigenetic, and gene regulation analyses to discover genes, pathways, and regulatory features relevant to age-related macular degeneration (AMD). (Image Credit: Adobe Stock/catalin)

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

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 AMD, or geographic atrophy (GA).

The study encompasses research spanning more than a decade 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.

"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."

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. From 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 findings point 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.

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.