Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma

PLoS Genet. 2012;8(4):e1002654. doi: 10.1371/journal.pgen.1002654. Epub 2012 Apr 26.

Abstract

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹⁸), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹⁰). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Publication types

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

MeSH terms

  • Alleles
  • Chromosomes, Human, Pair 8
  • Chromosomes, Human, Pair 9
  • Exfoliation Syndrome / genetics*
  • Genome-Wide Association Study*
  • Glaucoma, Open-Angle / genetics*
  • Homeodomain Proteins / genetics
  • Humans
  • Nerve Degeneration* / genetics
  • Nerve Degeneration* / pathology
  • Optic Nerve / pathology
  • Polymorphism, Single Nucleotide
  • RNA, Long Noncoding
  • RNA, Untranslated / genetics
  • Transforming Growth Factor beta* / genetics
  • Transforming Growth Factor beta* / metabolism

Substances

  • ANRIL long non-coding RNA, human
  • Homeodomain Proteins
  • RNA, Long Noncoding
  • RNA, Untranslated
  • SIX1 protein, human
  • Transforming Growth Factor beta

Grant support