Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci

Claire L Simpson; Robert Wojciechowski; Konrad Oexle; Federico Murgia; Laura Portas; Xiaohui Li; Virginie J M Verhoeven; Veronique Vitart; Maria Schache; S Mohsen Hosseini; Pirro G Hysi; Leslie J Raffel; Mary Frances Cotch; Emily Chew; Barbara E K Klein; Ronald Klein; Tien Yin Wong; Cornelia M van Duijn; Paul Mitchell; Seang Mei Saw; Maurizio Fossarello; Jie Jin Wang; DCCT/EDIC Research Group; Ozren Polašek; Harry Campbell; Igor Rudan; Ben A Oostra; André G Uitterlinden; Albert Hofman; Fernando Rivadeneira; Najaf Amin; Lennart C Karssen; Johannes R Vingerling; Angela Döring; Thomas Bettecken; Goran Bencic; Christian Gieger; H-Erich Wichmann; James F Wilson; Cristina Venturini; Brian Fleck; Phillippa M Cumberland; Jugnoo S Rahi; Chris J Hammond; Caroline Hayward; Alan F Wright; Andrew D Paterson; Paul N Baird; Caroline C W Klaver; Jerome I Rotter; Mario Pirastu; Thomas Meitinger; Joan E Bailey-Wilson; Dwight Stambolian

doi:10.1371/journal.pone.0107110

Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci

PLoS One. 2014 Sep 18;9(9):e107110. doi: 10.1371/journal.pone.0107110. eCollection 2014.

Authors

Claire L Simpson¹, Robert Wojciechowski², Konrad Oexle³, Federico Murgia⁴, Laura Portas⁴, Xiaohui Li⁵, Virginie J M Verhoeven⁶, Veronique Vitart⁷, Maria Schache⁸, S Mohsen Hosseini⁹, Pirro G Hysi¹⁰, Leslie J Raffel¹¹, Mary Frances Cotch¹², Emily Chew¹², Barbara E K Klein¹³, Ronald Klein¹³, Tien Yin Wong¹⁴, Cornelia M van Duijn¹⁵, Paul Mitchell¹⁶, Seang Mei Saw¹⁷, Maurizio Fossarello¹⁸, Jie Jin Wang¹⁹; DCCT/EDIC Research Group; Ozren Polašek²⁰, Harry Campbell²¹, Igor Rudan²¹, Ben A Oostra²², André G Uitterlinden²³, Albert Hofman²⁴, Fernando Rivadeneira²³, Najaf Amin¹⁵, Lennart C Karssen¹⁵, Johannes R Vingerling⁶, Angela Döring²⁵, Thomas Bettecken²⁶, Goran Bencic²⁷, Christian Gieger²⁸, H-Erich Wichmann²⁵, James F Wilson²¹, Cristina Venturini¹⁰, Brian Fleck²⁹, Phillippa M Cumberland³⁰, Jugnoo S Rahi³¹, Chris J Hammond¹⁰, Caroline Hayward⁷, Alan F Wright⁷, Andrew D Paterson⁹, Paul N Baird⁸, Caroline C W Klaver⁶, Jerome I Rotter⁵, Mario Pirastu⁴, Thomas Meitinger³², Joan E Bailey-Wilson¹, Dwight Stambolian³³

Collaborators

DCCT/EDIC Research Group:
S Genuth, D M Nathan, B Zinman, O Crofford, J Crandall, M Reid, J Brown-Friday, S Engel, J Sheindlin, H Martinez, H Shamoon, H Engel, M Phillips, R Gubitosi-Klug, L Mayer, S Pendegast, H Zegarra, D Miller, L Singerman, S Smith-Brewer, M Novak, J Quin, W Dahms, Saul Genuth, M Palmert, D Brillon, M E Lackaye, S Kiss, R Chan, V Reppucci, T Lee, M Heinemann, F Whitehouse, D Kruger, J K Jones, M McLellan, J D Carey, E Angus, A Thomas, A Galprin, R Bergenstal, M Johnson, M Spencer, K Morgan, D Etzwiler, D Kendall, Lloyd Paul Aiello, E Golden, A Jacobson, R Beaser, O Ganda, O Hamdy, H Wolpert, G Sharuk, P Arrigg, D Schlossman, J Rosenzwieg, L Rand, D M Nathan, M Larkin, M Ong, J Godine, E Cagliero, P Lou, K Folino, S Fritz, S Crowell, K Hansen, C Gauthier-Kelly, J Service, L Luttrell, S Caulder, M Lopes-Virella, J Colwell, J Soule, J Fernandes, K Hermayer, S Kwon, M Brabham, A Blevins, J Parker, D Lee, N Patel, C Pittman, P Lindsey, M Bracey, K Lee, M Nutaitis, A Farr, S Elsing, T Thompson, J Selby, T Lyons, S Yacoub-Wasef, M Szpiech, D Wood, R Mayfield, M Molitch, B Schaefer, L Jampol, A Lyon, M Gill, Z Strugula, L Kaminski, R Mirza, E Simjanoski, D Ryan, O Kolterman, G Lorenzi, W Sivitz, M Bayless, D Counts, S Johnsonbaugh, M Hebdon, P Salemi, R Liss, T Donner, J Gordon, R Hemady, A Kowarski, D Ostrowski, S Steidl, B Jones, W H Herman, C L Martin, R Pop-Busui, A Sarma, J Albers, E Feldman, K Kim, S Elner, G Comer, T Gardner, R Hackel, R Prusak, L Goings, A Smith, J Gothrup, P Titus, J Lee, M Brandle, L Prosser, D A Greene, M J Stevens, A K Vine, J Bantle, N Wimmergren, A Cochrane, T Olsen, E Steuer, P Rath, B Rogness, D Hainsworth, D Goldstein, S Hitt, J Giangiacomo, D S Schade, J L Canady, J E Chapin, L H Ketai C, S Braunstein, P A Bourne, S Schwartz, A Brucker, B J Maschak-Carey, L Baker, T Orchard, N Silvers, C Ryan, T Songer, B Doft, S Olson, R L Bergren, L Lobes, P Paczan Rath, D Becker, D Rubinstein, P W Conrad, S Yalamanchi, A Drash, A Morrison, M L Bernal, J Vaccaro-Kish, J Malone, P R Pavan, N Grove, M N Iyer, A F Burrows, E A Tanaka, R Gstalder, S Dagogo-Jack, C Wigley, H Ricks, A Kitabchi, M B Murphy, S Moser, D Meyer, A Iannacone, E Chaum, S Yoser, M Bryer-Ash, S Schussler, H Lambeth, P Raskin, S Strowig, B Zinman, A Barnie, R Devenyi, M Mandelcorn, M Brent, S Rogers, A Gordon, J Palmer, S Catton, J Brunzell, H Wessells, I H de Boer, J Hokanson, J Purnell, J Ginsberg, J Kinyoun, S Deeb, M Weiss, G Meekins, J Distad, L Van Ottingham, J Dupre, J Harth, D Nicolle, M Driscoll, J Mahon, C Canny, M May, J Lipps, A Agarwal, T Adkins, L Survant, R L Pate, G E Munn, R Lorenz, S Feman, N White, L Levandoski, I Boniuk, G Grand, M Thomas, D D Joseph, K Blinder, G Shah, Boniuk, Burgess, J Santiago, W Tamborlane, P Gatcomb, K Stoessel, K Taylor, J Goldstein, S Novella, H Mojibian, D Cornfeld, R Gubitosi-Klug, J Quin, P Gaston, M Palmert, R Trail, W Dahms, J Lachin, P Cleary, J Backlund, W Sun, B Braffett, K Klumpp, K Chan, L Diminick, D Rosenberg, B Petty, A Determan, D Kenny, B Rutledge, Naji Younes, Williams, L Dews, M Hawkins, C Cowie, J Fradkin, C Siebert, R Eastman, R Danis, S Gangaputra, S Neill, M Davis, L Hubbard, H Wabers, M Burger, J Dingledine, V Gama, R Sussman, M Steffes, J Bucksa, M Nowicki, B Chavers, D O'Leary, J Polak, A Harrington, L Funk, R Crow, B Gloeb, S Thomas, C O'Donnell, E Soliman, Z M Zhang, R Prineas, C Campbell, C Ryan, D Sandstrom, T Williams, M Geckle, E Cupelli, F Thoma, B Burzuk, T Woodfill, P Low, C Sommer, K Nickander, M Budoff, R Detrano, N Wong, M Fox, L Kim, R Oudiz, J Lima, D Bluemke, E Turkbey, R J van der Geest, C Liu, A Malayeri, A Jain, C Miao, H Chahal, R Jarboe, G Weir, M Espeland, B Klein, T Manolio, L Rand, D Singer, M Stern, A E Boulton, C Clark, R D'Agostino, M Lopes-Virella, W T Garvey, T J Lyons, A Jenkins, R Klein, G Virella, A Jaffa, Rickey Carter, D Lackland, M Brabham, D McGee, D Zheng, R K Mayfield, A Paterson, A Boright, S Bull, L Sun, S Scherer, B Zinman, J Maynard, R Natarajan, F Miao, L Zhang, Z Chen, D M Nathan

Affiliations

¹ National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States of America.
² National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States of America; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
³ Institute of Human Genetics, Technische Universität München, Munich, Germany.
⁴ Institute of Population Genetics, National Research Council of Italy, Sassari, Italy.
⁵ Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America.
⁶ Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
⁷ MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh, United Kingdom.
⁸ Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.
⁹ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, and DCCT/EDIC Research Group, The Diabetes Control and Complications Trial and Follow-up Study, The Biostatistics Center, The George Washington University, Rockville, Maryland, United States of America.
¹⁰ Department of Twin Research & Genetic Epidemiology, King's College London, St Thomas' Hospital, London, United Kingdom.
¹¹ Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
¹² Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
¹³ Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
¹⁴ Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; Singapore Eye Research Institute, National University of Singapore, Singapore, Singapore.
¹⁵ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
¹⁶ Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, Australia.
¹⁷ Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
¹⁸ Dipartimento di Scienze Chirurgiche, Clinica Oculistica Universita' degli studi di Cagliari, Cagliari, Italy.
¹⁹ Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, Australia.
²⁰ Croatian Centre for Global Health, University of Split Medical School, Split, Croatia.
²¹ Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
²² Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
²³ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, The Hague, the Netherlands.
²⁴ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, The Hague, the Netherlands.
²⁵ Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
²⁶ Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
²⁷ Department of Ophthalmology, Hospital "Sestre Milosrdnice", Zagreb, Croatia.
²⁸ Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany.
²⁹ Princess Alexandra Eye Pavilion, Edinburgh, United Kingdom.
³⁰ MRC Centre of Epidemiology for Child Health, Institute of Child Health, University College London, London, United Kingdom.
³¹ MRC Centre of Epidemiology for Child Health, Institute of Child Health, University College London, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom; Ulverscroft Vision Research Group, Institute of Child Health, University College London, London, United Kingdom.
³² Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
³³ Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Abstract

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Age of Onset
Aged
Aged, 80 and over
Alleles
Eye / physiopathology*
Female
Genetic Association Studies
Genetic Markers / genetics
Genetic Predisposition to Disease
Humans
Hyperopia / genetics*
Linkage Disequilibrium
Male
Middle Aged
Myopia / genetics*
Phenotype
Polymorphism, Single Nucleotide
White People / genetics

Substances

Genetic Markers

Abstract

Publication types

MeSH terms

Substances

Grants and funding