Age-related macular degeneration (AMD) is a leading cause of visual loss. It has a strong genetic basis and common haplotypes on chromosome (Chr)1 (CFH Y402H variant) and on Chr10 (near HTRA1/ARMS2) contribute most risk. Little is known about the early molecular and cellular processes in AMD and we hypothesised that analysing submacular tissue from older donors with genetic risk, but without clinical features of AMD, would provide new insights. Therefore, we used mass spectrometry-based quantitative proteomics to compare the proteins in human submacular stromal tissue punches from donors who were homozygous for high-risk alleles at either Chr1 or Chr10 to those from donors who had protective haplotypes at these loci, all without clinical features of AMD. Additional comparisons were made with tissue from donors who were homozygous for high-risk Chr1 alleles and had early AMD. The Chr1 and Chr10 risk groups shared common changes compared to the low-risk group, particularly increased levels of mast-cell specific proteases including tryptase, chymase and carboxypeptidase A3. Histological analyses of submacular tissue from donors with genetic risk of AMD, but without clinical features of AMD, and from donors with Chr1 risk and AMD, demonstrated increased mast cells, particularly the MCT variety, along with increased levels of denatured collagen, compared to tissue from low genetic risk donors. We conclude that increased mast cell infiltration of the inner choroid, degranulation and subsequent extracellular matrix remodelling are early events in AMD pathogenesis and represents a unifying mechanistic link between Chr1 and Chr10 mediated AMD.