OBJECTIVE: Geographic atrophy secondary to age-related macular degeneration (GA) is considered a single entity. This study aimed to determine whether there are GA subgroups that can be defined by their genotype and phenotype. DESIGN: Retrospective analysis of cross-sectional data. PARTICIPANTS: Individuals (196 eyes of 196 patients) 50 years or older with GA from the EYE-RISK database. METHODS: Participants were graded for the presence of each of the following fundus features on color fundus photography: large soft drusen, reticular pseudodrusen (RPD), refractile drusen, hyperpigmentation, location of atrophy (foveal vs extrafoveal) and multifocal lesions. Genotypes of thirty-three single nucleotide polymorphisms previously assigned to the complement, lipid metabolism or the extracellular matrix (ECM) pathways, and ARMS2, were also included, and genetic risk scores (GRS) for each of those three pathways calculated. Hierarchical cluster analysis was used to determine subgroups of participants defined by these features. The discriminative ability of genotype, phenotype or both for each subgroup was determined with 10-fold cross-validated areas under the curve (cvAUC) and the agreement between predicted and actual subgroup membership was assessed with calibration plots. MAIN OUTCOME MEASURES: Identification and characterization of GA subgroups based on their phenotype and genotype. RESULTS: Cluster analyses identified three subgroups of GA. Subgroup 1 was characterized by high complement GRS, frequently associated with large soft drusen and foveal atrophy; subgroup 2 generally showed low GRS, foveal atrophy and few drusen (any type); and subgroup 3 presented a high ARMS2 and ECM GRS, RPD and extrafoveal atrophy. There was a high discriminative ability between subgroups for the genotype (cvAUC>/=0.94) and modest for the phenotype (cvAUC<0.65), with good calibration. CONCLUSIONS: We identified three GA subgroups that differed mostly by their genotype. Atrophy location and drusen type were the most relevant phenotypic features.< Réduire