ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Hanriët Springelkamp, Adriana Iglesias, Gabriel Cuellar-Partida, Najaf Amin, Kathryn Burdon, Elisabeth Van Leeuwen, Puya Gharahkhani, Aniket Mishra, Sven Van Der Lee, Alex Hewitt, Fernando Rivadeneira, Ananth Viswanathan, Roger Wolfs, Nicholas Martin, Wishal Ramdas, Leonieke van Koolwijk, Craig Pennell, Johannes Vingerling, Jenny Mountain, André UitterlindenAlbert Hofman, Paul Mitchell, Hans Lemij, Jie Jin Wang, Caroline Klaver, David Mackey, Jamie Craig, Cornelia van Duijn, Stuart Macgregor

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)


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 (ß = 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 (ß = 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.

Original languageEnglish
Pages (from-to)2689-2699
Number of pages11
JournalHuman Molecular Genetics
Issue number9
Publication statusPublished - 1 May 2015


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