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Hum Mol Genet. 2015 May 1;24(9):2689-99. doi: 10.1093/hmg/ddv027. Epub 2015 Jan 30.

ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure.

Author information

1
Department of Ophthalmology, Department of Epidemiology and.
2
Department of Epidemiology and.
3
Statistical and.
4
School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS 7000, Australia.
5
School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS 7000, Australia, Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, VIC 3002, Australia.
6
Department of Epidemiology and Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands, Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, 2593 CE The Hague, The Netherlands.
7
NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK.
8
Department of Ophthalmology.
9
Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, QLD 4006, Australia.
10
School of Women's and Infants' Health, University of Western Australia, Crawley, WA 6009, Australia.
11
Telethon Kids Institute, Subiaco, WA 6008, Australia.
12
Department of Epidemiology and Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, 2593 CE The Hague, The Netherlands.
13
Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, NSW 2006, Australia.
14
Glaucoma Service, The Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands.
15
School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS 7000, Australia, Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, WA 6009, Australia and.
16
Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
17
Statistical and stuart.macgregor@qimrberghofer.edu.au.

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.

PMID:
25637523
DOI:
10.1093/hmg/ddv027
[Indexed for MEDLINE]

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