A new study partially funded by the National Institutes of Health (NIH) has provided insights into the genetic factors linked to reticular pseudodrusen (RPD), deposits in the eye that increase the risk of vision loss among people with age-related macular degeneration (AMD). The findings indicate that AMD is a complex condition with multiple subtypes, suggesting that new treatment approaches are needed.
Drusen, which are lipid-rich deposits in the retina, are commonly associated with AMD, a leading cause of irreversible vision loss in older adults. While some drusen formation occurs naturally with aging, an increased number raises AMD risk. Standard drusen form beneath the retinal pigmented epithelium (RPE), whereas reticular pseudodrusen develop above this layer and appear as clusters with a ribbon or dot-like pattern. The presence of RPD is linked to a higher chance of progressing to geographic atrophy, a late-stage disease where retinal cells deteriorate.
The research involved analyzing DNA from three groups: individuals with both AMD and RPD, those with AMD but no RPD, and a control group without either condition. Both groups with AMD had more gene variants previously connected to AMD compared to controls. In particular, known risk variants on chromosomes 1 and 10 were more common among those with AMD.
However, when comparing the two AMD groups directly, there was no significant difference in chromosome 1 variations related to complement H factor (CFH)—a gene tied to immune system regulation and inflammation—in patients with or without RPD. Previous studies have established CFH’s role in AMD; drugs targeting this pathway were approved by the FDA in 2023 but showed only modest benefits for slowing geographic atrophy.
Differences emerged on chromosome 10: those with both AMD and RPD had higher frequencies of specific variations here than those without RPD. These differences became more pronounced as the number of reticular pseudodrusen increased. The study pinpointed these associations near genes ARMS2 and HTRA1 and identified links involving HTRA1-AS1—a long non-coding RNA molecule believed to influence other genes’ functions.
"Our data show that these deposits of reticular pseudodrusen, present in some but not all AMD cases, are driven by pathways associated with chromosome 10 and not by genetic risk in other AMD-related genes such as those on chromosome 1," said Robyn Guymer, Ph.D., Centre for Eye Research Australia. She co-authored the report alongside Melanie Bahlo, Ph.D., from The Walter and Eliza Hall Institute of Medical Research and members of the Reticular Pseudodrusen Consortium.
Further analysis using eye scans indicated that chromosome 10 variants correlated with thinner retinal layers compared to controls. Researchers suggest these genetic differences may affect retinal structure but note additional research is required.
"This study reinforces that AMD is not one disease," said Emily Chew, M.D., head of NEI's Division of Epidemiology and Clinical Applications and co-author of the report. "Our findings highlight that different treatment approaches will be needed for different AMD subtypes."
The study received partial funding from NEI and principal support through a Synergy Grant from Australia's National Health and Medical Research Council.
