ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Hanriët Springelkamp; Adriana Iglesias; Gabriel Cuellar-Partida; Najaf Amin; Kathryn Burdon; Elisabeth Van Leeuwen; Puya Gharahkhani; Aniket Mishra; Sven Van Der Lee; Alex Hewitt; Fernando Rivadeneira; Ananth Viswanathan; Roger Wolfs; Nicholas Martin; Wishal Ramdas; Leonieke van Koolwijk; Craig Pennell; Johannes Vingerling; Jenny Mountain; André Uitterlinden; Albert Hofman; Paul Mitchell; Hans Lemij; Jie Jin Wang; Caroline Klaver; David Mackey; Jamie Craig; Cornelia van Duijn; Stuart Macgregor

doi:10.1093/hmg/ddv027

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure

Hanriët Springelkamp, Adriana Iglesias, Gabriel Cuellar-Partida, Najaf Amin, Kathryn Burdon, Elisabeth Van Leeuwen, Puya Gharahkhani, Aniket Mishra, Sven Van Der Lee, Alex Hewitt, Fernando Rivadeneira, Ananth Viswanathan, Roger Wolfs, Nicholas Martin, Wishal Ramdas, Leonieke van Koolwijk, Craig Pennell, Johannes Vingerling, Jenny Mountain, André UitterlindenAlbert Hofman, Paul Mitchell, Hans Lemij, Jie Jin Wang, Caroline Klaver, David Mackey, Jamie Craig, Cornelia van Duijn, Stuart Macgregor

College of Medicine and Public Health

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

64 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 RotterdamStudy I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a newlocus associated with IOP. The most significantly associated SNPwas rs58073046 (ß = 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 (ß = 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.

Original language	English
Pages (from-to)	2689-2699
Number of pages	11
Journal	Human Molecular Genetics
Volume	24
Issue number	9
DOIs	https://doi.org/10.1093/hmg/ddv027
Publication status	Published - 1 May 2015

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Springelkamp, H., Iglesias, A., Cuellar-Partida, G., Amin, N., Burdon, K., Van Leeuwen, E., Gharahkhani, P., Mishra, A., Van Der Lee, S., Hewitt, A., Rivadeneira, F., Viswanathan, A., Wolfs, R., Martin, N., Ramdas, W., van Koolwijk, L., Pennell, C., Vingerling, J., 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{4753dac5395c44a19a4a2358d79b8103,

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 RotterdamStudy I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a newlocus associated with IOP. The most significantly associated SNPwas rs58073046 ({\ss} = 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 ({\ss} = 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. ",

author = "Hanri{\"e}t Springelkamp and Adriana Iglesias and Gabriel Cuellar-Partida and Najaf Amin and Kathryn Burdon and {Van Leeuwen}, Elisabeth and Puya Gharahkhani and Aniket Mishra and {Van Der Lee}, Sven and Alex Hewitt and Fernando Rivadeneira and Ananth Viswanathan and Roger Wolfs and Nicholas Martin and Wishal Ramdas and {van Koolwijk}, Leonieke and Craig Pennell and Johannes Vingerling and Jenny Mountain and Andr{\'e} Uitterlinden and Albert Hofman and Paul Mitchell and Hans Lemij and Wang, {Jie Jin} and Caroline Klaver and David Mackey and Jamie Craig and {van Duijn}, Cornelia and Stuart Macgregor",

year = "2015",

month = may,

day = "1",

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, A, Cuellar-Partida, G, Amin, N, Burdon, K, Van Leeuwen, E, Gharahkhani, P, Mishra, A, Van Der Lee, S, Hewitt, A, Rivadeneira, F, Viswanathan, A, Wolfs, R, Martin, N, Ramdas, W, van Koolwijk, L, Pennell, C, Vingerling, J, Mountain, J, Uitterlinden, A, Hofman, A, Mitchell, P, Lemij, H, Wang, JJ, Klaver, C, Mackey, D, Craig, J, van Duijn, C & 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, Hanriët

AU - Iglesias, Adriana

AU - Cuellar-Partida, Gabriel

AU - Amin, Najaf

AU - Burdon, Kathryn

AU - Van Leeuwen, Elisabeth

AU - Gharahkhani, Puya

AU - Mishra, Aniket

AU - Van Der Lee, Sven

AU - Hewitt, Alex

AU - Rivadeneira, Fernando

AU - Viswanathan, Ananth

AU - Wolfs, Roger

AU - Martin, Nicholas

AU - Ramdas, Wishal

AU - van Koolwijk, Leonieke

AU - Pennell, Craig

AU - Vingerling, Johannes

AU - Mountain, Jenny

AU - Uitterlinden, André

AU - Hofman, Albert

AU - Mitchell, Paul

AU - Lemij, Hans

AU - Wang, Jie Jin

AU - Klaver, Caroline

AU - Mackey, David

AU - Craig, Jamie

AU - van Duijn, Cornelia

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 RotterdamStudy I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a newlocus associated with IOP. The most significantly associated SNPwas rs58073046 (ß = 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 (ß = 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.

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 RotterdamStudy I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a newlocus associated with IOP. The most significantly associated SNPwas rs58073046 (ß = 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 (ß = 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.

UR - http://www.scopus.com/inward/record.url?scp=84941992050&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddv027

DO - 10.1093/hmg/ddv027

M3 - Article

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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