Hageman and colleagues employed a “genetic outlier” approach to elucidate the specific, differential contributions of the CFH-CFHR5 and ARMS2/HTRA1 loci to AMD phenotype by studying patients and human donor eyes carrying risk at the Chr1 locus only, the Chr10 locus only, or no risk at either locus. The gene discussed is CFHR5; the disease is age-related macular degeneration.