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Original Investigation
May 23, 2019

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

Author Affiliations
  • 1Institute of Human Genetics, University of Regensburg, Regensburg, Germany
  • 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 3Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Regensburg, Regensburg, Germany
  • 4Cologne Center for Genomics, University of Cologne, Cologne, Germany
  • 5Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
  • 6Department of Ophthalmology, University of Bonn, Bonn, Germany
  • 7Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland
  • 8Neurobiology Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland
  • 9Casey Eye Institute, Oregon Health & Science University, Portland
  • 10Novartis Pharmaceutical Inc, Basel, Switzerland
  • 11Novartis Pharmaceutical Inc, Cambridge, Massachusetts
JAMA Ophthalmol. 2019;137(8):867-876. doi:10.1001/jamaophthalmol.2019.1318
Key Points

Question  Are there common genetic variants contributing to progression of geographic atrophy secondary to age-related macular degeneration?

Findings  This pooled analysis combines data from 4 independent studies assessing progression of geographic atrophy secondary to age-related macular degeneration. The correlation between square root–transformed geographic atrophy growth rate and more than 7 million genetic variants was estimated, and 2 gene loci with genome-wide significance were identified as geographic atrophy progression–associated candidates: protein arginine methyltransferase 6 (chromosome 1) and lanosterol synthase (chromosome 21).

Meaning  Gene prioritization within 2 identified loci as geographic atrophy progression–associated candidates, providing a basis for future functional studies exploring mechanisms of atrophic lesion growth.


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.