ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Henriet Springelkamp, Adriana I. Iglesias, Gabriel Cuellar-Partida, Najaf Amin, Kathryn P. Burdon, Elisabeth M. van Leeuwen, Puya Gharahkhani, Aniket Mishra, Sven J. van der Lee, Alex W. Hewitt, Fernando Rivadeneira, Ananth C. Viswanathan, Roger C. W. Wolfs, Nicholas G. Martin, Wishal D. Ramdas, Leonieke M. van Koolwijk, Craig E. Pennell, Johannes R. Vingerling, Jenny E. Mountain, Andre G. UitterlindenAlbert Hofman, Paul Mitchell, Hans G. Lemij, Jie Jin Wang, Caroline C. W. Klaver, David A. Mackey, Jamie E. Craig, Cornelia M. van Duijn, Stuart MacGregor*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 (? = 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 (? = 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.? The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
Original languageEnglish
Pages (from-to)2689-2699
JournalHuman Molecular Genetics
Issue number9
Publication statusPublished - 1 May 2015


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