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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 Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort ( n  = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 ( β  = 0.44,  P -value = 1.87 × 10 −8 , minor allele frequency = 0.12), 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 ( β  = 0.16,  P -value = 0.04). The SNP was also significantly associated with POAG in two independent case–control studies [ n  = 1225 cases and  n  = 4117 controls; odds ratio (OR) = 1.53,  P -value = 1.99 × 10 −8 ], especially with high-tension glaucoma (OR = 1.66,  P -value = 2.81 × 10 −9 ; for normal-tension glaucoma OR = 1.29,  P -value = 4.23 × 10 −2 ).  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 .

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure