ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

H. Springelkamp; A.I. Iglesias; G. Cuellar-Partida; N. Amin; K.P. Burdon; E.M. Van Leeuwen; P. Gharahkhani; A. Mishra; S.J. Van Der Lee; A.W. Hewitt; F. Rivadeneira; A.C. Viswanathan; R.C.W. Wolfs; N.G. Martin; W.D. Ramdas; L.M. Van Koolwijk; Craig Pennell; J.R. Vingerling; Jenny Mountain; A.G. Uitterlinden; A. Hofman; P. Mitchell; H.G. Lemij; J.J. Wang; C.C.W. Klaver; David Mackey; J.E. Craig; C.M. Van Duijn; S. Macgregor

doi:10.1093/hmg/ddv027

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

H. Springelkamp
, A.I. Iglesias
, G. Cuellar-Partida
, N. Amin
, K.P. Burdon
, E.M. Van Leeuwen
, P. Gharahkhani
, A. Mishra
, S.J. Van Der Lee
, A.W. Hewitt
, F. Rivadeneira
, A.C. Viswanathan
, R.C.W. Wolfs
, N.G. Martin
, W.D. Ramdas
, L.M. Van Koolwijk
, Craig Pennell
, J.R. Vingerling
, Jenny Mountain
, A.G. Uitterlinden

A. Hofman, P. Mitchell, H.G. Lemij, J.J. Wang, C.C.W. Klaver, David Mackey, J.E. Craig, C.M. Van Duijn, S. Macgregor

Research output: Contribution to journal › Article › peer-review

81 Citations (Scopus)

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 × 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.

© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

Original language	English
Pages (from-to)	2689-2699
Journal	Human Molecular Genetics
Volume	24
Issue number	9
Early online date	30 Jan 2015
DOIs	https://doi.org/10.1093/hmg/ddv027
Publication status	Published - 2015

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10.1093/hmg/ddv027

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Springelkamp, H., Iglesias, A. I., Cuellar-Partida, G., Amin, N., Burdon, K. P., Van Leeuwen, E. M., Gharahkhani, P., Mishra, A., Van Der Lee, S. J., Hewitt, A. W., Rivadeneira, F., Viswanathan, A. C., Wolfs, R. C. W., Martin, N. G., Ramdas, W. D., Van Koolwijk, L. M., Pennell, C., Vingerling, J. R., Mountain, J., ... Macgregor, S. (2015). ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure. Human Molecular Genetics, 24(9), 2689-2699. https://doi.org/10.1093/hmg/ddv027

@article{2852a471a1db4ad4a7c8360450c7deb8,

title = "ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure",

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 × 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. {\textcopyright} The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] ",

author = "H. Springelkamp and A.I. Iglesias and G. Cuellar-Partida and N. Amin and K.P. Burdon and \{Van Leeuwen\}, E.M. and P. Gharahkhani and A. Mishra and \{Van Der Lee\}, S.J. and A.W. Hewitt and F. Rivadeneira and A.C. Viswanathan and R.C.W. Wolfs and N.G. Martin and W.D. Ramdas and \{Van Koolwijk\}, L.M. and Craig Pennell and J.R. Vingerling and Jenny Mountain and A.G. Uitterlinden and A. Hofman and P. Mitchell and H.G. Lemij and J.J. Wang and C.C.W. Klaver and David Mackey and J.E. Craig and \{Van Duijn\}, C.M. and S. Macgregor",

year = "2015",

doi = "10.1093/hmg/ddv027",

language = "English",

volume = "24",

pages = "2689--2699",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "9",

}

Springelkamp, H, Iglesias, AI, Cuellar-Partida, G, Amin, N, Burdon, KP, Van Leeuwen, EM, Gharahkhani, P, Mishra, A, Van Der Lee, SJ, Hewitt, AW, Rivadeneira, F, Viswanathan, AC, Wolfs, RCW, Martin, NG, Ramdas, WD, Van Koolwijk, LM, Pennell, C, Vingerling, JR, Mountain, J, Uitterlinden, AG, Hofman, A, Mitchell, P, Lemij, HG, Wang, JJ, Klaver, CCW, Mackey, D, Craig, JE, Van Duijn, CM & Macgregor, S 2015, 'ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure', Human Molecular Genetics, vol. 24, no. 9, pp. 2689-2699. https://doi.org/10.1093/hmg/ddv027

TY - JOUR

T1 - ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

AU - Springelkamp, H.

AU - Iglesias, A.I.

AU - Cuellar-Partida, G.

AU - Amin, N.

AU - Burdon, K.P.

AU - Van Leeuwen, E.M.

AU - Gharahkhani, P.

AU - Mishra, A.

AU - Van Der Lee, S.J.

AU - Hewitt, A.W.

AU - Rivadeneira, F.

AU - Viswanathan, A.C.

AU - Wolfs, R.C.W.

AU - Martin, N.G.

AU - Ramdas, W.D.

AU - Van Koolwijk, L.M.

AU - Pennell, Craig

AU - Vingerling, J.R.

AU - Mountain, Jenny

AU - Uitterlinden, A.G.

AU - Hofman, A.

AU - Mitchell, P.

AU - Lemij, H.G.

AU - Wang, J.J.

AU - Klaver, C.C.W.

AU - Mackey, David

AU - Craig, J.E.

AU - Van Duijn, C.M.

AU - Macgregor, S.

PY - 2015

Y1 - 2015

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 (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. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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 (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. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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 -

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

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