Ophthalmology Retina, November 2021
Can geographic atrophy (GA) secondary to age-related macular degeneration (AMD) be separated into two or more partially distinct subtypes? Moreover, do these subtypes have different genetic associations? Using phenotypic cluster analyses, Keenan et al. found defined subtypes of GA. However, no significant genotype-phenotype associations were observed.
For this study, the researchers analyzed data from 598 participants (598 eyes) who had incident GA during follow-up in AREDS2 (Age-Related Eye Disease Study 2). Phenotypic features from fundus photographs were subjected to cluster analysis in cross-sectional and longitudinal analyses. Identified clusters were compared by four pathway-based genetic risk scores. The analyses were then repeated in reverse (i.e., clustering by genotype and comparison by phenotype).
Main outcome measures were the characteristics and quality of cluster solutions and the genotype-phenotype associations.
In clustering by phenotype, k-means identified two clusters (labeled A and B), while hierarchical clustering identified four (C-F). A-E membership differed principally by GA configuration but in relatively few other ways. In longitudinal phenotypic analyses, k-means identified two clusters that differed principally by smoking status (G, H). These three sets of cluster divisions were not similar to each other (r ≤ .20).
Moreover, pairwise cluster comparison by the four genetic risk scores demonstrated no significant differences (p > .05 for all).
In clustering by genotype, k-means identified two clusters (I, J). These differed principally at ARMS2, but no significant genotype-phenotype associations were observed (p > .05 for all).
Thus, the researchers concluded, “GA phenotypes may vary continuously across a spectrum, rather than consisting of distinct subtypes that arise from separate genetic etiologies.” This suggests that, for any eye with GA, clinicians are “unlikely to infer the main genetic driver of GA from these phenotypic characteristics alone.”
The original article can be found here.