University Of Tasmania

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ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

journal contribution
posted on 2023-05-18, 08:31 authored by Springelkamp, H, Iglesias, AI, Cuellar-Partida, G, Amin, N, Kathryn BurdonKathryn Burdon, van Leeuwen, EM, Gharahkhani, P, Mishra, A, van der Lee, SJ, Alexander HewittAlexander Hewitt, Rivadeneira, F, Viswanathan, AC, Wolfs, RC, Martin, NG, Ramdas, WD, van Koolwijk, LM, Pennell, CE, Vingerling, JR, Mountain, JE, Uitterlinden, AG, Hofman, A, Mitchell, P, Lemij, HG, Wang, JJ, Klaver, CC, David MackeyDavid Mackey, Craig, JE, van Duijn, CM, MacGregor, S
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.


Publication title

Human Molecular Genetics










Menzies Institute for Medical Research


Oxford University Press

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Copyright 2015 The Author

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Clinical health not elsewhere classified

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