ArticleJournal of ophthalmology2025
Genetically Prioritized Plasma Proteins as Candidate Therapeutic Targets for Dry Age-Related Macular Degeneration.
Article in Journal of ophthalmology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Authors and funding
7 authors.
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Abstract
Background: Dry age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly, yet effective treatments remain limited. This study aimed to identify putative causal plasma proteins linked to dry AMD through proteome-wide Mendelian randomization (MR) and genetic pleiotropy analyses. Methods: We performed proteome-wide MR analyses using protein quantitative trait loci (pQTL) data from the UK Biobank Pharma Proteomics Project (UKB-PPP) and genetic summary statistics for dry AMD from FinnGen R11. Replication analyses were conducted using pQTL data from the deCODE Genetics cohort and dry AMD GWAS data from the Million Veteran Program (MVP), all in individuals of European ancestry. To enhance robustness, we conducted additional sensitivity analyses using colocalization and summary data-based MR (SMR) approaches. Cell-type-specific expression profiles derived from single-cell RNA sequencing (scRNA-seq) data were used to prioritize candidate drug targets based on tissue relevance and druggability. Results: Discovery MR analysis identified 22 plasma proteins putatively associated with dry AMD. Replication MR tests and genetic pleiotropy analyses prioritized 12 proteins. Two retinal cell-specific genes were validated through scRNA-seq analysis. Druggability assessment confirmed C3 as an established AMD target and identified MASP1 and CFHR2 as complement pathway components with partial druggability. Notably, the remaining nine proteins represent novel pathways in dry AMD pathogenesis, four of which offer immediate drug-repurposing opportunities with approved agents, while five represent previously unexplored therapeutic candidates with high mechanistic plausibility. Conclusions: This study provides genetically supported therapeutic candidates for dry AMD and prioritizes candidates with high clinical potential, advancing therapeutic strategies for dry AMD.
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