TY - JOUR
T1 - ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure
AU - Springelkamp, Henriet
AU - Iglesias, Adriana I.
AU - Cuellar-Partida, Gabriel
AU - Amin, Najaf
AU - Burdon, Kathryn P.
AU - van Leeuwen, Elisabeth M.
AU - Gharahkhani, Puya
AU - Mishra, Aniket
AU - van der Lee, Sven J.
AU - Hewitt, Alex W.
AU - Rivadeneira, Fernando
AU - Viswanathan, Ananth C.
AU - Wolfs, Roger C. W.
AU - Martin, Nicholas G.
AU - Ramdas, Wishal D.
AU - van Koolwijk, Leonieke M.
AU - Pennell, Craig E.
AU - Vingerling, Johannes R.
AU - Mountain, Jenny E.
AU - Uitterlinden, Andre G.
AU - Hofman, Albert
AU - Mitchell, Paul
AU - Lemij, Hans G.
AU - Wang, Jie Jin
AU - Klaver, Caroline C. W.
AU - Mackey, David A.
AU - Craig, Jamie E.
AU - van Duijn, Cornelia M.
AU - MacGregor, Stuart
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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: journals.permissions@oup.com.
AB - 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: journals.permissions@oup.com.
U2 - 10.1093/hmg/ddv027
DO - 10.1093/hmg/ddv027
M3 - Article
C2 - 25637523
SN - 0964-6906
VL - 24
SP - 2689
EP - 2699
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 9
ER -