Authors:
Springelkamp H, Iglesias AI, Cuellar-Partida G, Amin N, Burdon KP, van Leeuwen EM, ... Mountain JE, et al.
Authors notes:
Hum Mol Genet. 2015;24(9):2689-99.
Keywords:
ARHGEF12, glaucoma, intraocular pressure, genetic variants, IOP, population
Abstract:
Primary open-angle glaucoma (POAG) is a blinding disease.
Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly heritable.
Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1.
However, these genes explain only a small part of the heritability of IOP and POAG.
We performed a genome-wide association study of IOP in the population-based RotterdamStudy I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes.
In this discovery cohort (n = 8105), we identified a newlocus associated with IOP.
The most significantly associated SNPwas rs58073046, within the gene ARHGEF12.
Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated.
The SNP was also significantly associated with POAG in two independent case-control studies [n = 1225 cases and n = 4117 controls; odds ratio, especially with high-tension glaucoma for normal-tension glaucoma.
ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation.
Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36).
In conclusion, this study identified a novel association between IOP and ARHGEF12.