A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy

Nat Genet. 2016 Jun;48(6):640-7. doi: 10.1038/ng.3546. Epub 2016 Apr 18.


Polypoidal choroidal vasculopathy (PCV), a subtype of 'wet' age-related macular degeneration (AMD), constitutes up to 55% of cases of wet AMD in Asian patients. In contrast to the choroidal neovascularization (CNV) subtype, the genetic risk factors for PCV are relatively unknown. Exome sequencing analysis of a Han Chinese cohort followed by replication in four independent cohorts identified a rare c.986A>G (p.Lys329Arg) variant in the FGD6 gene as significantly associated with PCV (P = 2.19 × 10(-16), odds ratio (OR) = 2.12) but not with CNV (P = 0.26, OR = 1.13). The intracellular localization of FGD6-Arg329 is distinct from that of FGD6-Lys329. In vitro, FGD6 could regulate proangiogenic activity, and oxidized phospholipids increased expression of FGD6. FGD6-Arg329 promoted more abnormal vessel development in the mouse retina than FGD6-Lys329. Collectively, our data suggest that oxidized phospholipids and FGD6-Arg329 might act synergistically to increase susceptibility to PCV.

MeSH terms

  • Cells, Cultured
  • China
  • Cohort Studies
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Ethnicity
  • Gene Expression Profiling
  • Guanine Nucleotide Exchange Factors / genetics*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Mutation, Missense*
  • Polymorphism, Single Nucleotide
  • Subcellular Fractions / metabolism
  • Wet Macular Degeneration / genetics*


  • FGD6 protein, human
  • Guanine Nucleotide Exchange Factors