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ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure


Springelkamp, H and Iglesias, AI and Cuellar-Partida, G and Amin, N and Burdon, KP and van Leeuwen, EM and Gharahkhani, P and Mishra, A and van der Lee, SJ and Hewitt, AW and Rivadeneira, F and Viswanathan, AC and Wolfs, RC and Martin, NG and Ramdas, WD and van Koolwijk, LM and Pennell, CE and Vingerling, JR and Mountain, JE and Uitterlinden, AG and Hofman, A and Mitchell, P and Lemij, HG and Wang, JJ and Klaver, CC and Mackey, DA and Craig, JE and van Duijn, CM and MacGregor, S, ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure, Human Molecular Genetics, 24, (9) pp. 2689-2699. ISSN 1460-2083 (2015) [Refereed Article]

Copyright Statement

Copyright 2015 The Author

DOI: doi:10.1093/hmg/ddv027


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.

Item Details

Item Type:Refereed Article
Keywords:glaucoma, genetics, genome-wide association, risk factors
Research Division:Biomedical and Clinical Sciences
Research Group:Ophthalmology and optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Burdon, KP (Professor Kathryn Burdon)
UTAS Author:Hewitt, AW (Professor Alex Hewitt)
UTAS Author:Mackey, DA (Professor David Mackey)
ID Code:99167
Year Published:2015
Web of Science® Times Cited:60
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-03-16
Last Modified:2017-11-06

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