Assessment of Novel Genome-Wide Significant Gene Loci and Lesion Growth in Geographic Atrophy Secondary to Age-Related Macular Degeneration

Abstract

IMPORTANCE Age-related macular degeneration (AMD) is a common threat to vision loss in individuals older than 50 years. While neovascular complications in AMD are treatable, there is currently no therapy for geographic atrophy secondary to AMD. Geographic atrophy lesion progression over time shows considerable interindividual variability, but little is known about prognostic factors. OBJECTIVE To elucidate the contribution of common genetic variants to geographic atrophy lesion growth. DESIGN, SETTING, AND PARTICIPANTS This pooled analysis combined 4 independent studies: the Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM) study, the Directional Spread in Geographic Atrophy (DSGA) study, the Age-Related Eye Disease Study (AREDS), and the Geographic Atrophy Treatment Evaluation (GATE) study. Each provided data for geographic atrophy lesion growth in specific designs. Patients with geographic atrophy secondary to AMD were recruited to these studies. Genotypes were retrieved through the database of Genotypes and Phenotypes (for AREDS) or generated at the Cologne Center for Genomics (for FAM, DSGA, and GATE). MAIN OUTCOMES The correlation between square root-transformed geographic atrophy growth rate and 7 596 219 genetic variants passing quality control was estimated using linear regression. The calculations were adjusted for known factors influencing geographic atrophy growth, such as the presence of bilateral geographic atrophy as well as the number of lesion spots and follow-up times. MAIN OUTCOMES AND MEASURES Slopes per allele, 95% CIs, and P values of genetic variants correlated with geographic atrophy lesion growth. RESULTS A total of 935 patients (mean [SD] age, 74.7 [7.8] years; 547 female participants [59.0%]) were included. Two gene loci with conservative genome-wide significance were identified. Each minor allele of the genome-wide associated variants increased the geographic atrophy growth rate by a mean of about 15% or 0.05 mm per year. Gene prioritization within each locus suggests the protein arginine methyltransferase 6 gene (PRMT6; chromosome 1; slope, 0.046 [95% CI, 0.026-0.066]; P = 4.09 × 10 −8) and the lanosterol synthase gene (LSS; chromosome 21; slope, 0.105 [95% CI, 0.068-0.143]; P = 4.07 × 10 −7) as the most likely progression-associated genes. CONCLUSIONS AND RELEVANCE These data provide further insight into the genetic architecture of geographic atrophy lesion growth. Geographic atrophy is a clinical outcome with a high medical need for effective therapy. The genes PRMT6 and LSS are promising candidates for future studies aimed at understanding functional aspects of geographic atrophy progression and also for designing novel and targeted treatment options.

Enlargement of Geographic Atrophy From First Diagnosis to End of Life

“…A 2019 genome-wide association study found novel SNPs specifically associated with GA enlargement: variants in PRMT6 (rs11184959) and LSS (rs2839127). 33 Jointly, these SNPs explained only 6% of the variation in GA enlargement.…”

Long-term retinal changes in progressive geographic atrophy

“…23 Currently there is no approved treatment to halt/restore degenerative changes caused by GA. Several genes have been found to show promise as being potential targets for gene therapy as well. 24,25 The success of future gene therapies and advanced rehabilitative therapies depend on the understanding of retinal structural changes, and quantitative analysis of retinal layers can help increase our understanding of the disease as well as reveal potential targets for treatment or intervention. It may also provide a way to objectively measure clinical response and outcomes of future therapies.…”

Association of complement C3 inhibitor pegcetacoplan with reduced photoreceptor degeneration beyond areas of geographic atrophy

“…Downstream of C3 cleavage, C3 fragments exert a variety of effector functions and C5 initiates membrane attack complex formation 9 . Assuming that the complement system also impacts GA progression rates (a so-far unproven hypothesis in the natural-history setting) 10 – 12 , multiple complement inhibitors are currently evaluated in clinical trials aiming to slow GA progression. These include pegcetacoplan (APL-2), which slowed GA progression in recent Phase 2 and 3 trials 13 – 15 .…”