A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants Academic Article uri icon


MeSH Major

  • Genome-Wide Association Study
  • Macular Degeneration


  • Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.


publication date

  • February 2016



  • Academic Article



  • eng

PubMed Central ID

  • PMC4745342

Digital Object Identifier (DOI)

  • 10.1038/ng.3448

PubMed ID

  • 26691988

Additional Document Info

start page

  • 134

end page

  • 43


  • 48


  • 2