An international team led by University of Manchester scientists has created the most detailed picture yet of how genetic differences shape the way the human eye works.
The breakthrough could help explain why millions of people develop sight‑threatening conditions such as age‑related macular degeneration (AMD), as well as rarer inherited eye diseases.
The research is published in Nature Communications today.
Epidemiological research predicts that AMD, a leading cause of visual impairment in adults , will affect 288 million people worldwide by 2040.
And rarer inherited eye disorders which interfere with cells in the retina that sense light and send visual signals to the brain include Stargardt disease, retinitis pigmentosa, and cone‑rod dystrophy.
The researchers analysed whole‑genome sequencing data alongside RNA profiles from 201 donated human eyes.
That allowed them to study two key tissues involved in vision: the neurosensory retina, which captures light, and the retinal pigment epithelium, which supports and nourishes it.
By comparing DNA differences with gene activity in these tissues, the researchers found over 1.4 million genetic signals that influence how genes are turned on or off, known as expression quantitative trait loci, or eQTLs.
The signals influence how nearly 10,000 genes behave in the retina and almost 4,000 genes in the retinal pigment epithelium.
Many of the genetic effects were found in regions of the genome that act as regulatory switches, helping to turn genes on or off.
The study also identified hundreds of individuals whose retinal gene activity was unusually high or low compared with typical patterns.
Among these "expression outliers," the researchers pinpointed nearly 300 rare genetic variants that could plausibly explain the unusual gene 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.
ogether, they accounted for around 28% of the outliers, offering new leads for understanding how rare mutations contribute to eye disease.
The findings provide an unprecedented resource for scientists studying the genetic roots of vision disorders, and are available to other researchers for access
They also offer a roadmap for future research into personalised treatments and earlier diagnosis.
Author Dr Jamie Ellingford, from The University of Manchester, said: "Our study marks 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."
PhD Student at The University of Manchester, Jacob Sampson, who performed the extensive computational analysis reported in the study, added: "We hope this dataset will accelerate discoveries across ophthalmology, genetics, and precision medicine.
"And we hope it will support efforts to identify individuals at risk of sight‑threatening disease before symptoms appear.
Prof Simon J. Clark from the University of Tübingen in Germany, said: "These sorts of fundamental discoveries are only possible by using very well characterised human donor material.
"We are incredibly lucky to have access to one of Europe's largest human eye donor repositories, founded originally in Manchester back in 2015.
"We remain forever grateful for the generosity of all those donors and their families who contributed over the years."
The team included scientists from The University of Manchester, Massachusetts Eye and Ear, Harvard Medical School, Broad Institute of Harvard and MIT, University of Tübingen, University of Southampton, Universitas Riau, Manchester University NHS Foundation Trust, and the European Bioinformatics Institute.
- The research was supported by the Macular Society, Fight For Sight, the Medical Research Council and the NIHR Manchester Biomedical Research Centre.
- The paper Paired DNA and RNA sequencing uncovers common 1 and rare genomic variants regulating gene 2 expression in the human retina is published in nature Communications and available here. DOI https://www.doi.org/10.1038/s41467-026-72979-4
