A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci

Nat Commun. 2018 Jun 11;9(1):2278. doi: 10.1038/s41467-018-04555-4.


Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10-8), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5-3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Cohort Studies
  • Ethnicity / genetics
  • Female
  • Formins
  • Gene Expression
  • Gene Knockdown Techniques
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Glaucoma, Open-Angle / genetics*
  • Humans
  • Intraocular Pressure / genetics
  • LIM-Homeodomain Proteins / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Middle Aged
  • Mutation
  • Polymorphism, Single Nucleotide
  • Proteins / genetics
  • Retinal Ganglion Cells / metabolism
  • Risk Factors
  • Transcription Factors / genetics
  • United Kingdom


  • FMNL2 protein, human
  • Formins
  • LIM homeobox transcription factor 1 beta
  • LIM-Homeodomain Proteins
  • Proteins
  • Transcription Factors