NEI Study Points to ‘Ground Zero’ for AMD Development

Newswise — National Eye Institute researchers studying human retinas discovered 87 target genes where a mix of environmental factors likely influence one’s risk of developing age-related macular degeneration (AMD), a leading cause of vision loss in people ages 65 and older. The target genes appear to be in locations where epigenetic mechanisms – processes that regulate the expression of the genes we are born with – contribute to a person developing AMD or not. The report published March 4 in Nature Communications.

“Our findings provide a framework for treatment approaches aimed at regulating gene-environment relationships and their contribution to AMD progression and pathology,” said the study’s lead investigator, Anand Swaroop, Ph.D., senior investigator in the Neurobiology, Neurodegeneration, and Repair Laboratory at the NEI, part of the National Institutes of Health.

These findings also point to the involvement of specific cellular parts (mitochondria) and cellular processes (oxidative metabolism and proteostasis) in AMD pathogenesis via changes in epigenome, he said. 

AMD is a complex, multifactor eye disease involving a combination of genetic susceptibility, age, and environmental factors. Smoking, for example, increases AMD risk. Consuming a diet plentiful in omega3-rich foods, such as salmon, decreases risk. On the genetic front, previous, large population-based genetic studies have identified 52 DNA variants among people with the disease. But such variants are largely in non-coding parts of DNA and many questions remain about how each variant contributes to AMD. 

The current study is the first to integrate an analysis of epigenetic and gene expression changes in the eye to get a picture of where and how so many complex factors might interact to give rise to AMD. 

Specifically, they studied 160 retinas from donors who had AMD. The retina is the light-sensing part of the eye whose cells die off in AMD patients, leading to vision loss. Each retina was analyzed for its genotype (its specific genetic makeup), messenger RNA (indicating gene expression), presence of the previously identified genetic variants, the 3D structure of its DNA and profiles of DNA methylation, a central epigenetic mechanism. 

DNA methylation generally turns genes “off” in two ways: by recruiting proteins that repress gene expression, or by inhibiting the binding of transcription factors to DNA, a key step involved in the protein-making process. In these two ways, DNA methylation regulates gene expression. 

DNA methylation patterns get established during development, acting as a kind of switch that helps generate all the different types of proteins in our bodies. Throughout our lifetimes, environmental factors such as ultraviolet radiation exposure, diet and exercise can disrupt these DNA methylation patterns, leading to changes in gene expression. Conversely, gene expression changes can also lead to changes in DNA methylation.

Meanwhile, non-coding genetic variants also contribute to DNA methylation patterns, independently, but also in connection with exposure to environmental factors.

Using multiple algorithms and approaches for sorting genetic information and traits (Mendelian randomization and colocalization), the researchers mapped DNA methylation and gene expression patterns with previously identified genetic variants. The results point to patterns that occur in retina under normal, non-disease conditions, as well as those that occur in relation to AMD. Doing so, they identified the 87 target genes that are modulated by DNA methylation, and that are likely involved in disease progression and pathology.

The study’s approach lays the groundwork for future investigations into other tissues to understand other complex diseases.

The research was supported by the NEI Intramural Research Program, and also by NEI grants R01 EY031424, P30 EY014104, and R01 EY028554.

Reference:

Advani, J., Mehta, P.A., Hamel, A.R. et al. QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration. Nat Commun 15, 1972 (2024). https://doi.org/10.1038/s41467-024-46063-8