PURPOSE. To test whether genes for drusen formation are independent of age-related macular degeneration (AMD) pathogenesis. METHODS. A genome-wide model-free linkage analysis was performed, using two semiquantitative drusen traits, size and type, on two sets of data: (1) 325 individuals (225 sib pairs) from the Beaver Dam Eye Study (BDES), and (2) 297 individuals (346 sib pairs) from the Family Age Related Maculopathy Study (FARMS). Apolipoprotein E (APOE) genotypes were used as a covariate in a multipoint sibpair analysis. RESULTS. The authors found evidence of linkage on 19q13.31 (D19S245), with size of drusen in both the BDES (P ϭ 0.0287) and the FARMS (P ϭ 0.0013; P ϭ 0.0005, combined). In the BDES, type showed linkage evidence on 3p24.3 (D3S1768; P ϭ 0.0189) and 3q25.1 (D3S2404; P ϭ 0.0141); the linkage on 3p24.3 was also found with size (D3S1768; P ϭ 0.0264). In the FARMS, size showed evidence of linkage at 5q33.3 (D5S820; P ϭ 0.0021), 14q32.33 (D14S1007; P ϭ 0.0013), and 16p13.13 (D16S2616; P ϭ 0.0015) and type at 21q21.2 (D21S2052; P ϭ 0.0070). For size in the FARMS, there was a small increase in P-value at marker D19S245 from 0.0044 to 0.0111, and from 0.0044 to 0.0064, when the 4-carrier and the 3-carrier genotype were the covariates, respectively. CONCLUSIONS. The results show that APOE effects may be mediated early in the progression of ARM to AMD and thus may not be detected by standard genome scans for more severe disease. (Invest Ophthalmol Vis Sci. 2005;46:3081-3088