Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration

J Hum Genet. 2020 Aug;65(8):657-665. doi: 10.1038/s10038-020-0750-x. Epub 2020 Apr 10.


Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly population. To accelerate the understanding of the genetics of AMD, we conducted a meta-analysis of genome-wide association studies (GWAS) combining data from the International AMD Genomics Consortium AMD-2016 GWAS (16,144 advanced AMD cases and 17,832 controls), AMD-2013 GWAS (17,181 cases and 60,074 controls), and new data on 4017 AMD cases and 14,984 controls from Genetic Epidemiology Research on Aging study. We identified 12 novel AMD loci near or within C4BPA-CD55, ZNF385B, ZBTB38, NFKB1, LINC00461, ADAM19, CPN1, ACSL5, CSK, RLBP1, CLUL1, and LBP. We then replicated the associations of the novel loci in independent cohorts, UK Biobank (5860 cases and 126,726 controls) and FinnGen (1266 cases and 47,560 control). In general, the concordance in effect sizes was very high (correlation in effect size estimates 0.89), 11 of 12 novel loci were in the expected direction, 5 were associated with AMD at a nominal significance level, and rs3825991 (near gene RLBP1) after Bonferroni correction. We identified an additional 21 novel genes using a gene-based test. Most of the novel genes are expressed in retinal tissue and could be involved in the pathogenesis of AMD (i.e., complement, inflammation, and lipid pathways). These findings enhance our understanding of the genetic architecture of AMD and shed light on the biological process underlying AMD pathogenesis.

Publication types

  • Meta-Analysis

MeSH terms

  • ADAM Proteins / genetics
  • Acute-Phase Proteins / genetics
  • CD55 Antigens / genetics
  • Carrier Proteins / genetics
  • Coenzyme A Ligases / genetics
  • Complement C4b-Binding Protein / genetics
  • Databases, Genetic
  • Eye Proteins / genetics
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Macular Degeneration / genetics*
  • Membrane Glycoproteins / genetics
  • NF-kappa B p50 Subunit / genetics
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Repressor Proteins / genetics
  • Retina / metabolism
  • Retina / pathology


  • 11-cis-retinal-binding protein
  • Acute-Phase Proteins
  • C4BPA protein, human
  • CD55 Antigens
  • CLUL1 protein, human
  • Carrier Proteins
  • Complement C4b-Binding Protein
  • Eye Proteins
  • Membrane Glycoproteins
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • Nuclear Proteins
  • Repressor Proteins
  • ZBTB38 protein, human
  • ZNF385B protein, human
  • lipopolysaccharide-binding protein
  • ADAM Proteins
  • ADAM19 protein, human
  • Coenzyme A Ligases
  • ACSL5 protein, human