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- Title
ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure.
- Authors
Springelkamp, Henriët; Iglesias, Adriana I.; Cuellar-Partida, Gabriel; Amin, Najaf; Burdon, Kathryn P.; van Leeuwen, Elisabeth M.; Gharahkhani, Puya; Mishra, Aniket; van der Lee, Sven J.; Hewitt, Alex W.; Rivadeneira, Fernando; Viswanathan, Ananth C.; Wolfs, Roger C. W.; Martin, Nicholas G.; Ramdas, Wishal D.; van Koolwijk, Leonieke M.; Pennell, Craig E.; Vingerling, Johannes R.; Mountain, Jenny E.; Uitterlinden, André G.
- Abstract
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 x 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 x 10-8], especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 x 10-9; for normal-tension glaucoma OR = 1.29, P-value = 4.23 x 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
Human Molecular Genetics, 2015, Vol 24, Issue 9, p2689
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddv027