Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Henriët Springelkamp; René Höhn; Aniket Mishra; Pirro G Hysi; Chiea-Chuen Khor; Stephanie J Loomis; Jessica N Cooke Bailey; Jane Gibson; Gudmar Thorleifsson; Sarah F Janssen; Xiaoyan Luo; Wishal D Ramdas; Eranga Vithana; Monisha E Nongpiur; Grant W Montgomery; Liang Xu; Jenny E Mountain; Puya Gharahkhani; Yi Lu; Najaf Amin; Lennart C Karssen; Kar-Seng Sim; Elisabeth M van Leeuwen; Adriana I Iglesias; Virginie J M Verhoeven; Michael A Hauser; Seng-Chee Loon; Dominiek D G Despriet; Abhishek Nag; Cristina Venturini; Paul G Sanfilippo; Arne Schillert; Jae H Kang; John Landers; Fridbert Jonasson; Angela J Cree; Leonieke M E van Koolwijk; Fernando Rivadeneira; Emmanuelle Souzeau; Vesteinn Jonsson; Geeta Menon; Blue Mountains Eye Study—GWAS group; Robert N Weinreb; Paulus T V M de Jong; Ben A Oostra; André G Uitterlinden; Albert Hofman; Sarah Ennis; Unnur Thorsteinsdottir; Kathryn P Burdon; NEIGHBORHOOD Consortium; Wellcome Trust Case Control Consortium 2 (WTCCC2); Timothy D Spector; Alireza Mirshahi; Seang-Mei Saw; Johannes R Vingerling; Yik-Ying Teo; Jonathan L Haines; Roger C W Wolfs; Hans G Lemij; E-Shyong Tai; Nomdo M Jansonius; Jost B Jonas; Ching-Yu Cheng; Tin Aung; Ananth C Viswanathan; Caroline C W Klaver; Jamie E Craig; Stuart Macgregor; David A Mackey; Andrew J Lotery; Kari Stefansson; Arthur A B Bergen; Terri L Young; Janey L Wiggs; Norbert Pfeiffer; Tien-Yin Wong; Louis R Pasquale; Alex W Hewitt; Cornelia M van Duijn; Christopher J Hammond

doi:10.1038/ncomms5883

Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

Nat Commun. 2014 Sep 22:5:4883. doi: 10.1038/ncomms5883.

Authors

Henriët Springelkamp¹, René Höhn², Aniket Mishra³, Pirro G Hysi⁴, Chiea-Chuen Khor⁵, Stephanie J Loomis⁶, Jessica N Cooke Bailey⁷, Jane Gibson⁸, Gudmar Thorleifsson⁹, Sarah F Janssen¹⁰, Xiaoyan Luo¹¹, Wishal D Ramdas¹², Eranga Vithana¹³, Monisha E Nongpiur¹⁴, Grant W Montgomery¹⁵, Liang Xu¹⁶, Jenny E Mountain¹⁷, Puya Gharahkhani³, Yi Lu³, Najaf Amin¹⁸, Lennart C Karssen¹⁸, Kar-Seng Sim¹⁹, Elisabeth M van Leeuwen¹⁸, Adriana I Iglesias¹⁸, Virginie J M Verhoeven¹, Michael A Hauser²⁰, Seng-Chee Loon²¹, Dominiek D G Despriet¹², Abhishek Nag⁴, Cristina Venturini²², Paul G Sanfilippo²³, Arne Schillert²⁴, Jae H Kang²⁵, John Landers²⁶, Fridbert Jonasson²⁷, Angela J Cree²⁸, Leonieke M E van Koolwijk¹⁸, Fernando Rivadeneira²⁹, Emmanuelle Souzeau²⁶, Vesteinn Jonsson³⁰, Geeta Menon³¹; Blue Mountains Eye Study—GWAS group; Robert N Weinreb³², Paulus T V M de Jong³³, Ben A Oostra³⁴, André G Uitterlinden²⁹, Albert Hofman³⁵, Sarah Ennis³⁶, Unnur Thorsteinsdottir³⁷, Kathryn P Burdon²⁶; NEIGHBORHOOD Consortium; Wellcome Trust Case Control Consortium 2 (WTCCC2); Timothy D Spector⁴, Alireza Mirshahi², Seang-Mei Saw³⁸, Johannes R Vingerling¹, Yik-Ying Teo³⁹, Jonathan L Haines⁷, Roger C W Wolfs¹², Hans G Lemij⁴⁰, E-Shyong Tai⁴¹, Nomdo M Jansonius⁴², Jost B Jonas⁴³, Ching-Yu Cheng¹³, Tin Aung¹⁴, Ananth C Viswanathan⁴⁴, Caroline C W Klaver¹, Jamie E Craig²⁶, Stuart Macgregor³, David A Mackey⁴⁵, Andrew J Lotery²⁸, Kari Stefansson³⁷, Arthur A B Bergen⁴⁶, Terri L Young¹¹, Janey L Wiggs⁶, Norbert Pfeiffer², Tien-Yin Wong¹³, Louis R Pasquale⁴⁷, Alex W Hewitt²³, Cornelia M van Duijn¹⁸, Christopher J Hammond⁴

Collaborators

Paul Mitchell, Jie Jin Wang, Elena Rochtchina, John Attia, Rodney Scott, Elizabeth G Holliday, Tien-Yin Wong, Paul N Baird, Jing Xie, Michael Inouye, Ananth Viswanathan, Xueling Sim, R Rand Allingham, Murray H Brilliant, Donald L Budenz, Jessica N Cooke Bailey, William G Christen, John Fingert, David S Friedman, Douglas Gaasterland, Terry Gaasterland, Jonathan L Haines, Michael A Hauser, Jae Hee Kang, Peter Kraft, Richard K Lee, Paul R Lichter, Yutao Liu, Stephanie J Loomis, Sayoko E Moroi, Louis R Pasquale, Margaret A Pericak-Vance, Anthony Realini, Julia E Richards, Joel S Schuman, William K Scott, Kuldev Singh, Arthur J Sit, Douglas Vollrath, Robert N Weinreb, Janey L Wiggs, Gadi Wollstein, Donald J Zack, Kang Zhang, Peter Donnelly, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Peter Donnelly, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Ines Barroso, Panos Deloukas, Christopher G Mathew, Jenefer M Blackwell, Matthew A Brown, Aiden Corvin, Chris C A Spencer

Affiliations

¹ 1] Department of Ophthalmology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [2] Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
² Department of Ophthalmology, University Medical Center Mainz, Mainz 55131, Germany.
³ Department of Genetics and Computational Biology, Statistical Genetics, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Queensland 4006, Australia.
⁴ Department of Twin Research and Genetic Epidemiology, King's College London, London WC2R 2LS, UK.
⁵ 1] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119077, Singapore [2] Division of Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
⁶ Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA.
⁷ 1] Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA [2] Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
⁸ Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
⁹ deCODE/Amgen, Reykjavik 101, Iceland.
¹⁰ Department of Clinical and Molecular Ophthalmogenetics, The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam 1105 BA, the Netherlands.
¹¹ Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina 27710, USA.
¹² Department of Ophthalmology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
¹³ 1] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119077, Singapore [2] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore [3] Duke-National University of Singapore, Graduate Medical School, Singapore 169857, Singapore.
¹⁴ 1] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119077, Singapore [2] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore.
¹⁵ Department of Genetics and Computational Biology, Molecular Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Queensland 4006, Australia.
¹⁶ 1] Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China [2] Beijing Ophthalmology and Visual Science Key Lab, Beijing 100730, China.
¹⁷ Telethon Institute for Child Health Research, Subiaco, Western Australia 6008, Australia.
¹⁸ Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
¹⁹ Division of Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
²⁰ Departments of Medicine and Ophthalmology, Duke University Medical Center, Durham, North Carolina 27710, USA.
²¹ Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119077, Singapore.
²² 1] Department of Twin Research and Genetic Epidemiology, King's College London, London WC2R 2LS, UK [2] UCL Institute of Ophthalmology, London EC1V 9EL, UK.
²³ Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia.
²⁴ Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck 23562, Germany.
²⁵ Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
²⁶ Department of Ophthalmology, Flinders University, Adelaide, South Australia 5042, Australia.
²⁷ 1] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland [2] Department of Ophthalmology, Landspitali National University Hospital, Reykjavik 101, Iceland.
²⁸ Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
²⁹ 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [2] Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [3] Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, The Hague 2593 CE, The Netherlands.
³⁰ Department of Ophthalmology, Landspitali National University Hospital, Reykjavik 101, Iceland.
³¹ Department of Ophthalmology, Frimley Park Hospital NHS Foundation Trust, Frimley GU16 7UJ, UK.
³² Department of Ophthalmology and Hamilton Glaucoma Center, University of California, San Diego, California 92093, USA.
³³ 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [2] Department of Retinal Signal Processing, Netherlands Institute for Neuroscience, Amsterdam 1105 BA, The Netherlands [3] Department of Ophthalmology, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands [4] Department of Ophthalmology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
³⁴ Department of Clinical Genetics, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.
³⁵ 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [2] Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, The Hague 2593 CE, The Netherlands.
³⁶ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
³⁷ 1] deCODE/Amgen, Reykjavik 101, Iceland [2] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
³⁸ 1] Department of Ophthalmology, National University of Singapore and National University Health System, Singapore 119077, Singapore [2] Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 168751, Singapore [3] Duke-National University of Singapore, Graduate Medical School, Singapore 169857, Singapore [4] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore.
³⁹ 1] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore [2] Department of Statistics and Applied Probability, National University of Singapore, Singapore 119077, Singapore.
⁴⁰ Glaucoma Service, The Rotterdam Eye Hospital, Rotterdam 3011 BH, The Netherlands.
⁴¹ 1] Duke-National University of Singapore, Graduate Medical School, Singapore 169857, Singapore [2] Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore 117597, Singapore [3] Department of Medicine, National University of Singapore and National University Health System, Singapore 119077, Singapore.
⁴² Department of Ophthalmology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands.
⁴³ 1] Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China [2] Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Seegartenklinik Heidelberg, Heidelberg 69117, Germany.
⁴⁴ NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London EC1V 2PD, UK.
⁴⁵ 1] Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria 3002, Australia [2] Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia 6009, Australia.
⁴⁶ 1] Department of Clinical and Molecular Ophthalmogenetics, The Netherlands Institute for Neuroscience (NIN), Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam 1105 BA, the Netherlands [2] Department of Ophthalmology, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands [3] Department of Clinical Genetics, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
⁴⁷ 1] Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA [2] Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

Abstract

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

Publication types

Meta-Analysis
Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Asian People / genetics
Case-Control Studies
Gene Expression Profiling
Gene Frequency
Genome-Wide Association Study*
Genotype
Glaucoma / ethnology
Glaucoma / genetics*
Glaucoma / physiopathology*
Humans
Optic Disk / pathology
Optic Nerve / pathology
Phenotype
Polymorphism, Single Nucleotide
White People / genetics

Abstract

Publication types

MeSH terms

Grants and funding