Felix Grassmann1,2, Sebastian Harsch1, Caroline Brandl1,3, Christina Kiel1, Peter Nürnberg4,5, Mohammad R Toliat4, Monika Fleckenstein6, Maximilian Pfau6, Steffen Schmitz-Valckenberg6, Frank G Holz6, Emily Y Chew7, Anand Swaroop8, Rinki Ratnapriya8, Michael L Klein9, Zufar Mulyukov10, Parisa Zamiri11, Bernhard H F Weber1. 1. Institute of Human Genetics, University of Regensburg, Regensburg, Germany. 2. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 3. Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Regensburg, Regensburg, Germany. 4. Cologne Center for Genomics, University of Cologne, Cologne, Germany. 5. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. 6. Department of Ophthalmology, University of Bonn, Bonn, Germany. 7. Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland. 8. Neurobiology Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland. 9. Casey Eye Institute, Oregon Health & Science University, Portland. 10. Novartis Pharmaceutical Inc, Basel, Switzerland. 11. Novartis Pharmaceutical Inc, Cambridge, Massachusetts.
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.
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.
Authors: Eric M Moult; Yingying Shi; Liang Wang; Siyu Chen; Nadia K Waheed; Giovanni Gregori; Philip J Rosenfeld; James G Fujimoto Journal: Ophthalmol Sci Date: 2022-04-14
Authors: Tiarnan D L Keenan; Neal L Oden; Elvira Agrón; Traci E Clemons; Alice Henning; Lars G Fritsche; Wai T Wong; Emily Y Chew Journal: Ophthalmol Retina Date: 2021-07-26