Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
25637523
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.
The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
DATE PUBLISHED
2015 May 1
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2014/11/04
accepted 2015/01/21
aheadofprint 2015/01/30
entrez 2015/02/01 06:00
pubmed 2015/02/01 06:00
medline 2015/12/23 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Springelkamp H Springelkamp Henriët H Department of Ophthalmology, Department of Epidemiology and.
Iglesias AI Iglesias Adriana I AI Department of Epidemiology and.
Cuellar-Partida G Cuellar-Partida Gabriel G Statistical and.
Amin N Amin Najaf N Department of Epidemiology and.
Burdon KP Burdon Kathryn P KP School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, TAS 7000, Australia.
van Leeuwen EM van Leeuwen Elisabeth M EM Department of Epidemiology and.
Gharahkhani P Gharahkhani Puya P Statistical and.
Mishra A Mishra Aniket A Statistical and.
van der Lee SJ van der Lee Sven J SJ Department of Epidemiology and.
Hewitt AW Hewitt Alex W AW 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.
Rivadeneira F Rivadeneira Fernando F 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.
Viswanathan AC Viswanathan Ananth C AC NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK.
Wolfs RC Wolfs Roger C W RC Department of Ophthalmology.
Martin NG Martin Nicholas G NG Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, QLD 4006, Australia.
Ramdas WD Ramdas Wishal D WD Department of Ophthalmology.
van Koolwijk LM van Koolwijk Leonieke M LM Department of Epidemiology and.
Pennell CE Pennell Craig E CE School of Women's and Infants' Health, University of Western Australia, Crawley, WA 6009, Australia.
Vingerling JR Vingerling Johannes R JR Department of Ophthalmology, Department of Epidemiology and.
Mountain JE Mountain Jenny E JE Telethon Kids Institute, Subiaco, WA 6008, Australia.
Uitterlinden AG Uitterlinden André G AG 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.
Hofman A Hofman Albert A Department of Epidemiology and Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, 2593 CE The Hague, The Netherlands.
Mitchell P Mitchell Paul P Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, NSW 2006, Australia.
Lemij HG Lemij Hans G HG Glaucoma Service, The Rotterdam Eye Hospital, 3011 BH Rotterdam, The Netherlands.
Wang JJ Wang Jie Jin JJ Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, NSW 2006, Australia.
Klaver CC Klaver Caroline C W CC Department of Ophthalmology, Department of Epidemiology and.
Mackey DA Mackey David A DA 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.
Craig JE Craig Jamie E JE Department of Ophthalmology, Flinders University, Adelaide, SA 5042, Australia.
van Duijn CM van Duijn Cornelia M CM Department of Epidemiology and.
MacGregor S MacGregor Stuart S Statistical and stuart.macgregor@qimrberghofer.edu.au.
INVESTIGATORS
JOURNAL
VOLUME: 24
ISSUE: 9
TITLE: Human molecular genetics
ISOABBREVIATION: Hum. Mol. Genet.
YEAR: 2015
MONTH: May
DAY: 1
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1460-2083
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Hum Mol Genet
COUNTRY: England
ISSNLINKING: 0964-6906
NLMUNIQUEID: 9208958
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Aged
Female
Gene Expression
Genetic Association Studies
Genetic Predisposition to Disease
Genome-Wide Association Study
Glaucoma physiopathology
Glaucoma, Open-Angle physiopathology
Humans physiopathology
Intraocular Pressure genetics
Male genetics
Meta-Analysis as Topic genetics
Middle Aged genetics
Polymorphism, Single Nucleotide genetics
Protein Interaction Mapping genetics
Protein Interaction Maps genetics
Rho Guanine Nucleotide Exchange Factors metabolism
SUPPLEMENTARY MESH
SUPPLMESHNAME SUPPLMESHTYPE
Glaucoma, Primary Open Angle Disease
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 ARHGEF12 protein, human
0 Rho Guanine Nucleotide Exchange Factors
OTHER ID's