Huang, KevinKevinHuangSchofield, CherylCherylSchofieldNguy, TrungTrungNguyDere, RandallRandallDereWolowski, VincentVincentWolowskiSiebourg-Polster, JulianeJulianeSiebourg-PolsterDieckmann, AndreasAndreasDieckmannGarweg, Justus G.Justus G.GarwegChang, MichaelMichaelChangHonigberg, LeeLeeHonigbergHackney, JasonJasonHackneyIndjeian, Vahan BVahan BIndjeian2025-05-262025-05-262025-04-24https://boris-portal.unibe.ch/handle/20.500.12422/210224Background Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is one of the main causes of blindness in the elderly population, but the molecular pathophysiology is difficult to study due to limited access to retinal tissue. We investigated aqueous humor (AH) as an accessible surrogate for studying retinal pathophysiology.Methods We applied affinity-based Olink proteomics on AH samples obtained from 30 non-AMD control, 30 intermediate AMD (iAMD) and 28 GA subjects to identify AH biomarkers associated with GA. Quantile normalization was applied to the Olink data, followed by differential abundance analysis using the limma R package. To contextualize our findings, we cross-referenced the identified proteins to gene expression datasets and AH proteomics data from diabetic retinopathy (DR) subjects.Results Our differential abundance analysis reveals 82 significantly altered proteins in GA compared to non-AMD control. Cross-referencing with gene expression datasets indicates a majority of them are robustly expressed in the retina, particularly in retinal pigment epithelium cells. Comparison with AH proteomics data from DR subjects reveals both unique and shared biomarkers between GA and DR. Integrating these findings, we identify SMOC2 and IL-6 as top candidate GA biomarkers, warranting further investigation.Conclusions Our integrative analysis demonstrates a robust framework for AH biomarker discovery and identifies SMOC2 and IL-6 as promising biomarkers for GA. Our findings underscore the potential of AH proteomic profiling to advance our understanding of the underlying pathophysiology of retinal diseases.Age-related macular degeneration (AMD) is an eye disease in which central vision can be blurred. We investigated whether proteins in the aqueous humor, a fluid found in the front of the eye, could be used to identify people with geographic atrophy (GA), a late form of AMD, and shed light on how the disease progresses. We found 82 proteins that differed in people with GA compared to those without. Many of these proteins are expressed in the eye. Our research shows that analyzing aqueous humor can provide valuable insights into the biology of retinal diseases such as GA, and could be used to help identify people with the disease and the stage of their disease.en600 - Technology::610 - Medicine & healtharticle10.48620/881724027496610.1038/s43856-025-00862-2