An international team has created the most detailed picture yet of how genetic differences shape the way the human eye works, uncovering how both common and rare DNA variants influence gene activity in the eye and potentially contribute to blinding diseases.
The breakthrough could help explain why millions of people develop conditions such as age-related macular degeneration (AMD), as well as rarer inherited eye diseases, including Stargardt disease, retinitis pigmentosa (RP), and cone rod dystrophy.
The research, published in Nature Communications,1 analysed paired DNA and RNA sequencing data from 201 donated human eyes.
By comparing DNA differences with gene activity in the neurosensory retina and the retinal pigment epithelium, researchers were able to identify more than 1.4 million genetic signals that alter how retinal genes are switched on and off.
The signals influence how nearly 10,000 genes behave in the retina and almost 4,000 genes in the retinal pigment epithelium.
By understanding these patterns, we move closer to uncovering the biological mechanisms that drive heritable vision loss and to developing more targeted therapies
Researchers also uncovered evidence that rare non-coding mutations, structural variants, and copy number changes may play a larger role in inherited eye disease than previously recognised. The team detected more than 1,000 unusual gene expression events and linked nearly 300 rare genetic variants to disrupted retinal activity.
These variants included rare changes in parts of DNA that don’t code for proteins, as well as bigger structural shifts and differences in how many copies of certain DNA segments a person has.
These findings could help explain why many patients with inherited retinal disorders still do not receive a definitive genetic diagnosis, despite advances in genome sequencing.
Author Dr Jamie Ellingford, from The University of Manchester, described the study as marking a “major step toward decoding the complex genetic architecture of the human eye”. “And it opens the door to new strategies for protecting and restoring vision in the future. It reveals how both common and rare genetic differences shape the way they are expressed in the human retina.
“By understanding these patterns, we move closer to uncovering the biological mechanisms that drive heritable vision loss and to developing more targeted therapies.”
Reference
- Sampson J, Segrè AV, Ellingford JM, et al. Paired DNA and RNA sequencing uncovers common and rare variation regulating human retinal gene expression. Nat Commun. 2026;17:4595. doi: 10.1038/s41467-026-72979-4.
