Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma

Nat Genet. 2014 Oct;46(10):1120-1125. doi: 10.1038/ng.3079. Epub 2014 Aug 31.

Abstract

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics*
  • ATP Binding Cassette Transporter 1 / metabolism
  • Aged
  • Aged, 80 and over
  • Australia
  • Cohort Studies
  • Female
  • Gene Expression
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Glaucoma, Open-Angle / genetics*
  • Glaucoma, Open-Angle / metabolism
  • Humans
  • Hydro-Lyases / genetics*
  • Immunoblotting
  • Male
  • Meta-Analysis as Topic
  • Microfilament Proteins / genetics*
  • Microfilament Proteins / metabolism
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Risk Factors
  • United States

Substances

  • ABCA1 protein, human
  • AFAP1 protein, human
  • ATP Binding Cassette Transporter 1
  • Microfilament Proteins
  • Hydro-Lyases
  • GDPmannose 4,6-dehydratase