Reticular pseudodrusen (RPD) have long been recognized as a critical imaging phenotype in age-related macular degeneration (AMD) — one associated with faster progression, worse functional outcomes, and a heightened risk of late disease. Yet despite its clinical importance, the biological basis of RPD has remained elusive. A major international effort, published in Nature Communications , now provides the most definitive genetic evidence to date that RPD represents a distinct, genetically driven subtype within the AMD spectrum.
Involving 14 cohorts and more than 6,300 individuals, the study pooled OCT-based and multimodal imaging assessments of RPD alongside ~8 million single nucleotide polymorphisms (SNPs) per cohort to perform the largest RPD-focused genome-wide association meta-analysis to date. After rigorous quality control and harmonization of phenotype definitions, the team analyzed 2,165 AMD+/RPD+ and 4,181 AMD+/RPD– individuals.
The meta-analysis revealed a single genome-wide significant locus for RPD, located on chromosome 10 at the ARMS2/HTRA1 region. This region has long been implicated in AMD risk, but this new analysis clarifies that ARMS2/HTRA1 variation specifically drives susceptibility to RPD, distinguishing it from conventional soft drusen phenotypes.
Importantly, the RPD locus also contains the long non-coding RNA HTRA1-AS1, whose functional interactions with the region’s protein-coding genes may further influence disease biology.
One of the study’s most clinically intuitive findings was the dose-response relationship between RPD risk allele dosage and RPD lesion burden. Individuals carrying two copies of the RPD risk allele had markedly greater RPD lesion extent compared to heterozygotes or non-carriers. This provides tangible biological reinforcement for what clinicians observe in practice: patients with severe RPD often behave differently — and progress differently — from those with conventional drusen.
To further probe causality, the team performed whole-genome sequencing on individuals with “extreme RPD” phenotypes, identifying both rare variants and haplotype patterns within the ARMS2/HTRA1 region that reinforce its central role in RPD pathogenesis.
These findings, taken together, strongly support the concept that RPD is not simply another imaging manifestation of AMD, but a subtype with a unique genetic architecture. This distinction may ultimately shape clinical trial stratification, risk modeling, and therapeutic targeting.
The work provides a framework for understanding why RPD-positive patients often present with different progression trajectories and poorer functional metrics. As multimodal imaging and AI-driven RPD detection become standard, integrating genetic insights such as these will be key to refining prognosis and personalizing AMD care.
Involving 14 cohorts and more than 6,300 individuals, the study pooled OCT-based and multimodal imaging assessments of RPD alongside ~8 million single nucleotide polymorphisms (SNPs) per cohort to perform the largest RPD-focused genome-wide association meta-analysis to date. After rigorous quality control and harmonization of phenotype definitions, the team analyzed 2,165 AMD+/RPD+ and 4,181 AMD+/RPD– individuals.
The meta-analysis revealed a single genome-wide significant locus for RPD, located on chromosome 10 at the ARMS2/HTRA1 region. This region has long been implicated in AMD risk, but this new analysis clarifies that ARMS2/HTRA1 variation specifically drives susceptibility to RPD, distinguishing it from conventional soft drusen phenotypes.
Importantly, the RPD locus also contains the long non-coding RNA HTRA1-AS1, whose functional interactions with the region’s protein-coding genes may further influence disease biology.
One of the study’s most clinically intuitive findings was the dose-response relationship between RPD risk allele dosage and RPD lesion burden. Individuals carrying two copies of the RPD risk allele had markedly greater RPD lesion extent compared to heterozygotes or non-carriers. This provides tangible biological reinforcement for what clinicians observe in practice: patients with severe RPD often behave differently — and progress differently — from those with conventional drusen.
To further probe causality, the team performed whole-genome sequencing on individuals with “extreme RPD” phenotypes, identifying both rare variants and haplotype patterns within the ARMS2/HTRA1 region that reinforce its central role in RPD pathogenesis.
These findings, taken together, strongly support the concept that RPD is not simply another imaging manifestation of AMD, but a subtype with a unique genetic architecture. This distinction may ultimately shape clinical trial stratification, risk modeling, and therapeutic targeting.
The work provides a framework for understanding why RPD-positive patients often present with different progression trajectories and poorer functional metrics. As multimodal imaging and AI-driven RPD detection become standard, integrating genetic insights such as these will be key to refining prognosis and personalizing AMD care.
