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Purpose: Studies of progression from early to advanced AMD (geographic atrophy or macular neovascularization) generally have focused on genetic factors or ocular pathology that increase risk of progression to identify etiologic mechanisms and therapeutic targets. An alternative approach is to study older individuals that resist the development of AMD pathology, thus identifying potential protective factors.

Methods: In our baseline examination from the Amish Eye Study, we identified a cohort of 79 “resistant” individuals aged over 75 who lacked four OCT-derived biomarkers associated with the progression to advanced AMD (high central drusen volume in 3mm circle, intraretinal hyperreflective foci, hyporeflective drusen cores, and subretinal drusenoid deposits). Within this group, a subset of 50 individuals was further identified, each carrying at least one risk allele in one of the four most strongly AMD-associated loci (CFH, ARMS2/HTRA1, C3, C2/CFB). We organized these subjects into computationally tractable subpedigrees (15 for the larger group and 9 for the subset). Our statistical analysis involved a two-stage approach. Initially, we performed a genome-wide genetic linkage analysis across the identified subpedigrees. Subsequently, in regions with suggestive linkage (LOD*> 2), we conducted regional association analysis in a 10 Mb region centered on the linkage peak using the 79 “resistant” and 124 non-resistant individuals over age 75.

Results: Suggestive evidence for genetic linkage in non-parametric linkage analysis using MERLIN was found in one region on chromosome 2 (LOD*= 2.4 at 103.9 Mb in a 9 pedigree subset with …