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.
authors: Department of Ophthalmology, Department of Epidemiology and.
authors: Henriët
authors: H
authors: Springelkamp
authors: Department of Epidemiology and.
authors: Adriana I
authors: AI
authors: Iglesias
authors: Statistical and.
authors: Gabriel
authors: G
authors: Cuellar-Partida
authors: Department of Epidemiology and.
authors: Najaf
authors: N
authors: Amin
authors: School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS 7000, Australia.
authors: Kathryn P
authors: KP
authors: Burdon
authors: Department of Epidemiology and.
authors: Elisabeth M
authors: EM
authors: van Leeuwen
authors: Statistical and.
authors: Puya
authors: P
authors: Gharahkhani
authors: Statistical and.
authors: Aniket
authors: A
authors: Mishra
authors: Department of Epidemiology and.
authors: Sven J
authors: SJ
authors: van der Lee
authors: 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.
authors: Alex W
authors: AW
authors: Hewitt
authors: 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.
authors: Fernando
authors: F
authors: Rivadeneira
authors: NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK.
authors: Ananth C
authors: AC
authors: Viswanathan
authors: Department of Ophthalmology.
authors: Roger C W
authors: RC
authors: Wolfs
authors: Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, QLD 4006, Australia.
authors: Nicholas G
authors: NG
authors: Martin
authors: Department of Ophthalmology.
authors: Wishal D
authors: WD
authors: Ramdas
authors: Department of Epidemiology and.
authors: Leonieke M
authors: LM
authors: van Koolwijk
authors: School of Women's and Infants' Health, University of Western Australia, Crawley, WA 6009, Australia.
authors: Craig E
authors: CE
authors: Pennell
authors: Department of Ophthalmology, Department of Epidemiology and.
authors: Johannes R
authors: JR
authors: Vingerling
authors: Telethon Kids Institute, Subiaco, WA 6008, Australia.
authors: Jenny E
authors: JE
authors: Mountain
authors: 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.
authors: André G
authors: AG
authors: Uitterlinden
authors: Department of Epidemiology and Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, 2593 CE The Hague, The Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors: Paul
authors: P
authors: Mitchell
authors: Glaucoma Service, The Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands.
authors: Hans G
authors: HG
authors: Lemij
authors: Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, NSW 2006, Australia.
authors: Jie Jin
authors: JJ
authors: Wang
authors: Department of Ophthalmology, Department of Epidemiology and.
authors: Caroline C W
authors: CC
authors: Klaver
authors: 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.
authors: David A
authors: DA
authors: Mackey
authors: Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
authors: Jamie E
authors: JE
authors: Craig
authors: Department of Epidemiology and.
authors: Cornelia M
authors: CM
authors: van Duijn
authors: Statistical and stuart.macgregor@qimrberghofer.edu.au.
authors: Stuart
authors: S
authors: MacGregor
mesh_terms: D000368:Aged; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005901:Glaucoma / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology*; D005902:Glaucoma, Open-Angle / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C577222:ARHGEF12 protein, human; D064067:Rho Guanine Nucleotide Exchange Factors