Significance Genome-wide association studies have identified two major risk loci for age-related macular degeneration (AMD) on chromosome (Chr) 1 and Chr10. Here, we use proteomics to analyze submacular stromal tissue punches from older eye donors without AMD, comparing tissue from donors who were homozygous for high-risk alleles at Chr1 or Chr10 with tissue from donors with low risk at these two loci. A common change found in Chr1/Chr10–risk eyes was increased mast cell proteases, and immunohistochemistry confirmed the presence of increased mast cell numbers. This study, therefore, provides a unifying mechanistic link between Chr1 and Chr10 risk and suggests that mast cell infiltration of the choroid and degranulation are early events in AMD pathogenesis.