International study sheds light on inherited eye disease

An international team led by scientists from the The University of Manchester, including Prof. Simon J. Clark from IOR in Tübingen 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 today in Nature Communications. Epidemiological studies predict that AMD, a leading cause of visual impairment in adults, will affect 288 million people worldwide by 2040. Other inherited retinal disorders include Stargardt disease, Retinitis pigmentosa, and cone-rod dystrophy.

Mapping genetic activity in the human retina

The researchers analysed whole-genome sequencing data alongside RNA profiles from 201 donated human eyes. This enabled the team 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 identified more than 1.4 million genetic signals that influence how genes are turned on or off, known as expression quantitative trait loci (eQTLs). These signals affect the behaviour of nearly 10,000 genes in the retina and almost 4,000 genes in the retinal pigment epithelium. Many of the effects were found in genomic regions that act as regulatory switches controlling gene activity.

Rare variants provide new clues

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 included rare changes in non-coding DNA regions, larger structural genomic changes, and differences in the number of DNA segment copies. Together, these variants accounted for around 28% of the outliers, offering important new insights into how rare mutations contribute to eye disease. The findings provide an unprecedented resource for scientists studying the genetic roots of vision disorders and are expected to support future research into personalised treatments and earlier diagnosis.

Researchers highlight future impact

Lead author Dr. Jamie Ellingford from the The University of Manchester said:

“Our study marks a major step toward decoding the complex genetic architecture of the human eye" - “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 genes 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.”

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." - “We also hope it will support efforts to identify individuals at risk of sight-threatening disease before symptoms appear.”

Importance of donor eye research

Prof Simon J. Clark from the University of Tübingen, who was involved in the project and publication, highlighted the importance of donor material for advancing vision research:

“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.”

International collaboration and funding

The team included scientists from the Massachusetts Eye and Ear, Harvard Medical School, Broad Institute, 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 and rare genomic variants regulating gene expression in the human retina, is published in Nature Communications.