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.
Researchers performed a genome-wide association study of intraocular pressure in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms ( SNPs ) imputed to 1000 Genomes.
In this discovery cohort ( n=8,105 ) researchers have identified a new locus associated with intraocular pressure. The most significantly associated SNP was rs58073046 ( beta=0.44, p-value=1.87x10-8, minor allele frequency=0.12 ), within the gene ARHGEF12.
Independent replication in five population-based studies ( n=7,471 ) resulted in an effect size in the same direction that was significantly associated ( beta=0.16, p-value=0.04 ).
The SNP was also significantly associated with POAG in two independent case-control studies ( n=1,225 cases and n=4,117 controls; OR=1.53, p-value=1.99x10-8 ), especially with high-tension glaucoma ( OR=1.66, p-value=2.81x10-9; for normal-tension glaucoma OR=1.29, p-value=4.23x10-2 ).
ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in intraocular pressure regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2, and GAS7 pathway to Mendelian POAG genes ( MYOC, OPTN, WDR36 ). ( Xagena )
Springelkamp H et al, Hum Mol Genet 2015; Epub ahead of print