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  • Genetics of Geographic Atrophy

    By Jean Shaw
    Selected by Andrew P. Schachat, MD

    Journal Highlights

    Ophthalmology Retina, November 2021

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    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.