van Koolwijk, LM;
Ramdas, WD;
Ikram, MK;
Jansonius, NM;
Pasutto, F;
Hysi, PG;
Macgregor, S;
... van Duijn, CM; + view all
(2012)
Common genetic determinants of intraocular pressure and primary open-angle glaucoma.
PLoS Genet
, 8
(5)
, Article e1002611. 10.1371/journal.pgen.1002611.
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Abstract
Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma and is the only target for current glaucoma therapy. The genetic factors which determine IOP are largely unknown. We performed a genome-wide association study for IOP in 11,972 participants from 4 independent population-based studies in The Netherlands. We replicated our findings in 7,482 participants from 4 additional cohorts from the UK, Australia, Canada, and the Wellcome Trust Case-Control Consortium 2/Blue Mountains Eye Study. IOP was significantly associated with rs11656696, located in GAS7 at 17p13.1 (p=1.4×10(-8)), and with rs7555523, located in TMCO1 at 1q24.1 (p=1.6×10(-8)). In a meta-analysis of 4 case-control studies (total N = 1,432 glaucoma cases), both variants also showed evidence for association with glaucoma (p=2.4×10(-2) for rs11656696 and p=9.1×10(-4) for rs7555523). GAS7 and TMCO1 are highly expressed in the ciliary body and trabecular meshwork as well as in the lamina cribrosa, optic nerve, and retina. Both genes functionally interact with known glaucoma disease genes. These data suggest that we have identified two clinically relevant genes involved in IOP regulation.
| Type: | Article |
|---|---|
| Title: | Common genetic determinants of intraocular pressure and primary open-angle glaucoma. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pgen.1002611 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pgen.1002611 |
| Language: | English |
| Additional information: | © 2012 van Koolwijk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The Rotterdam Study is funded by the Erasmus Medical Center and the Erasmus University Rotterdam, The Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The generation and management of genome-wide association studies (GWAS) genotype data for the Rotterdam Study is supported by The Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), The Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810. The Erasmus Rucphen Family (ERF) Study is supported by the Center for Medical Systems Biology (CMSB) of NGI, the Internationale Stichting voor Alzheimer Onderzoek (ISAO, 04516), Hersenstichting Nederland (HSN, 150207), and the Alzheimer Association (IRRG0514359). The ophthalmic part of the Rotterdam and ERF Studies is supported by The Netherlands Organization for Health Research and Development (ZonMw) grant 2200.0035; Lijf en Leven, Krimpen a/d Lek; MD Fonds, Utrecht; Oogfonds Nederland, Utrecht; Stichting Nederlands Oogheelkundig Onderzoek, Nijmegen/Rotterdam; Swart van Essen, Rotterdam; Netherlands Organisation for Scientific Research (NWO); Bevordering van Volkskracht, Rotterdam; Blindenhulp, The Hague; Blindenpenning, Amsterdam; Stichting Winckel-Sweep, Utrecht; Landelijke Stichting voor Blinden en Slechtzienden (LSBS), Utrecht; Rotterdamse Vereniging voor Blindenbelangen, Rotterdam; OOG, The Hague; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB), Doorn; The Rotterdam Eye Hospital Research Foundation (Stichting Wetenschappelijk Onderzoek Het Oogziekenhuis [SWOO] Prof. Dr. H. J. Flieringa, Rotterdam); Laméris Ootech BV, Nieuwegein; Topcon Europe BV, Capelle aan de IJssel, all in The Netherlands; and Heidelberg Engineering, Dossenheim, Germany. The King's College London authors acknowledge funding from the Guide Dogs for the Blind Association, Wellcome Trust, the EU MyEuropia Marie Curie Research Training Network, the European Community's FP7 (HEALTH-F2-2008-201865-GEFOS), ENGAGE (HEALTH-F4-2007-201413), FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), National Institutes of Health (NIH)/National Eye Institute (NEI) grant 1RO1EY018246 (PI TLY), and genotyping by the NIH Center for Inherited Disease Research (CIDR) (PI TLY). The study also receives support from the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust partnering KCL. CJH is an NIHR Senior Research Fellow. The Australian Twin Registry is supported by an Australian National Health and Medical Research Council (NHMRC) Enabling Grant (2004–2009). We also thank the following organisations for their financial support: Clifford Craig Medical Research Trust, Ophthalmic Research Institute of Australia (ORIA), American Health Assistance Foundation (AHAF), Peggy and Leslie Cranbourne Foundation, Foundation for Children, NHMRC project grant 350415 (2005–2007), Jack Brockhoff Foundation, NEI Project Grant RO1 EY 018246-01 (2007–2010) (PI TLY). Genotyping for part of the Australian sample was funded by an NHMRC Medical Genomics Grant. Genotyping for the remainder was performed by CIDR as part of an NEI/NIH project grant. Australian sample imputation analyses were carried out on the Genetic Cluster Computer which is financially supported by The Netherlands Scientific Organization (NWO 480-05-003). DAM is a recipient of the Pfizer Australia Senior Research Fellowship. SM is supported by an Australian NHMRC Career Development Award. The Wellcome Trust Case-Control Consortium 2 project was funded by the Wellcome Trust (085475/B/08/Z and 085475/Z/08/Z), the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHSFT, and UCL Institute of Ophthalmology. This project included genotyping of the Blue Mountains Eye Study, which was also supported in part by the Australian National Health and Medical Research Council (512423). We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02, and of the UK National Blood Service controls funded by the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| Keywords: | Aged, Aged, 80 and over, Case-Control Studies, Ciliary Body, Female, Genome-Wide Association Study, Glaucoma, Open-Angle, Humans, Intraocular Pressure, Male, Middle Aged, Nerve Tissue Proteins, Optic Nerve, Polymorphism, Single Nucleotide, Trabecular Meshwork |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1349062 |
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