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      Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error

      1 , 2 , 3 , 4 , 5 , 6 , 7 , 7 , 1 , 2 , 8 , 1 , 2 , 8 , 1 , 2 , 9 , 10 , 11 , 12 , 10 , 13 , 14 , 15 , 16 , 17 , 17 , 18 , 18 , 19 , 20 , 21 , 22 , 22 , 23 , 24 , 12 , 9 , 9 , 25 , 25 , 26 , 27 , 28 , 29 , 13 , 30 , 10 , 31 , 31 , 32 , 29 , 29 , 33 , 34 , 33 , 35 , 36 , 33 , 36 , CREAM, 23andMe Research Team, UK Biobank Eye and Vision Consortium, 36 , 16 , 37 , 9 , 38 , 39 , 39 , 40 , 41 , 1 , 2 , 42 , 43 , 44 , 42 , 43 , 2 , 45 , 46 , 2 , 46 , 47 , 2 , 46 , 47 , 1 , 48 , 49 , 50 , 51 , 52 , 53 , 4 , 54 , 42 , 55 , 56 , 57 , 55 , 6 , 58 , 12 , 59 , 60 , 59 , 61 , 62 , 63 , 64 , 65 , 40 , 66 , 67 , 68 , 69 , 65 , 70 , 71 , 23 , 72 , 73 , 23 , 72 , 73 , 4 , 74 , 15 , 75 , 76 , 23 , 33 , 2 , 2 , 4 , 9 , 29 , 77 , 17 , 55 , 26 , 7 , 6 , 1 , 2 , 78

      Nature genetics

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          Abstract

          Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants, increased the established independent signals from 37 to 161 and revealed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and functional contributions to refractive error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes elicited novel mechanisms such as rod and cone bipolar synaptic neurotransmission, anterior segment morphology, and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade, and delineate potential pathobiological molecular drivers.

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          Most cited references 89

          • Record: found
          • Abstract: found
          • Article: not found

          The UCSC Known Genes.

          The University of California Santa Cruz (UCSC) Known Genes dataset is constructed by a fully automated process, based on protein data from Swiss-Prot/TrEMBL (UniProt) and the associated mRNA data from Genbank. The detailed steps of this process are described. Extensive cross-references from this dataset to other genomic and proteomic data were constructed. For each known gene, a details page is provided containing rich information about the gene, together with extensive links to other relevant genomic, proteomic and pathway data. As of July 2005, the UCSC Known Genes are available for human, mouse and rat genomes. The Known Genes serves as a foundation to support several key programs: the Genome Browser, Proteome Browser, Gene Sorter and Table Browser offered at the UCSC website. All the associated data files and program source code are also available. They can be accessed at http://genome.ucsc.edu. The genomic coverage of UCSC Known Genes, RefSeq, Ensembl Genes, H-Invitational and CCDS is analyzed. Although UCSC Known Genes offers the highest genomic and CDS coverage among major human and mouse gene sets, more detailed analysis suggests all of them could be further improved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Population stratification and spurious allelic association.

            Great efforts and expense have been expended in attempts to detect genetic polymorphisms contributing to susceptibility to complex human disease. Concomitantly, technology for detection and scoring of single nucleotide polymorphisms (SNPs) has undergone rapid development, extensive catalogues of SNPs across the genome have been constructed, and SNPs have been increasingly used as a means for investigation of the genetic causes of complex human diseases. For many diseases, population-based studies of unrelated individuals--in which case-control and cohort studies serve as standard designs for genetic association analysis--can be the most practical and powerful approach. However, extensive debate has arisen about optimum study design, and considerable concern has been expressed that these approaches are prone to population stratification, which can lead to biased or spurious results. Over the past decade, a great shift has been noted, away from case-control and cohort studies, towards family-based association designs. These designs have fewer problems with population stratification but have greater genotyping and sampling requirements, and data can be difficult or impossible to gather. We discuss past evidence for population stratification on genotype-phenotype association studies, review methods to detect and account for it, and present suggestions for future study design and analysis.
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              • Record: found
              • Abstract: found
              • Article: not found

              Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral.

              Genetic testing for hereditary cancer syndromes contributes to the medical management of patients who may be at increased risk of one or more cancers. BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer is one such widely used test. However, clinical testing methods with high sensitivity for deleterious mutations in these genes also detect many unclassified variants, primarily missense substitutions. We developed an extension of the Grantham difference, called A-GVGD, to score missense substitutions against the range of variation present at their position in a multiple sequence alignment. Combining two methods, co-occurrence of unclassified variants with clearly deleterious mutations and A-GVGD, we analysed most of the missense substitutions observed in BRCA1. A-GVGD was able to resolve known neutral and deleterious missense substitutions into distinct sets. Additionally, eight previously unclassified BRCA1 missense substitutions observed in trans with one or more deleterious mutations, and within the cross-species range of variation observed at their position in the protein, are now classified as neutral. The methods combined here can classify as neutral about 50% of missense substitutions that have been observed with two or more clearly deleterious mutations. Furthermore, odds ratios estimated for sets of substitutions grouped by A-GVGD scores are consistent with the hypothesis that most unclassified substitutions that are within the cross-species range of variation at their position in BRCA1 are also neutral. For most of these, clinical reclassification will require integrated application of other methods such as pooled family histories, segregation analysis, or validated functional assay.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                1 May 2018
                28 May 2018
                June 2018
                28 November 2018
                : 50
                : 6
                : 834-848
                Affiliations
                [1 ]Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands
                [2 ]Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
                [3 ]Department of Epidemiology and Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
                [4 ]Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
                [5 ]Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
                [6 ]Section of Academic Ophthalmology, School of Life Course Sciences, King’s College London, London, UK
                [7 ]23andMe, Inc., Mountain View, California, USA
                [8 ]Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
                [9 ]Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, Madison, Wisconsin, USA
                [10 ]Centre for Quantitative Medicine, DUKE-National University of Singapore, Singapore
                [11 ]Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
                [12 ]NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
                [13 ]Ocular Epidemiology Research Group, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
                [14 ]Department of Ophthalmology, University Hospital Bern, Inselspital, University of Bern, Bern, Switzerland
                [15 ]Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany
                [16 ]Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan
                [17 ]Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
                [18 ]Estonian Genome Center, University of Tartu, Tartu, Estonia
                [19 ]Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
                [20 ]Department of Public Health, University of Helsinki, Helsinki, Finland
                [21 ]Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany
                [22 ]Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
                [23 ]Centre for Eye Research Australia, Ophthalmology, Department of Surgery, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
                [24 ]Department of Ophthalmology, Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
                [25 ]Program in Genetics and Genome Biology, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
                [26 ]School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK
                [27 ]Department of Population Health Sciences, Bristol Medical School, Bristol, UK
                [28 ]Department of Statistics and Applied Probability, National University of Singapore, Singapore
                [29 ]Saw Swee Hock School of Public Health, National University Health Systems, National University of Singapore, Singapore
                [30 ]Department of Health Service Research, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
                [31 ]Statistics Support Platform, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
                [32 ]Life Sciences Institute, National University of Singapore, Singapore
                [33 ]MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK
                [34 ]Faculty of Medicine, University of Split, Split, Croatia
                [35 ]Department of Ophthalmology, Sisters of Mercy University Hospital, Zagreb, Croatia
                [36 ]Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK
                [37 ]Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
                [38 ]Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
                [39 ]Department of Bioinformatics, Erasmus Medical Center, Rotterdam, The Netherlands
                [40 ]Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
                [41 ]Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
                [42 ]Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA
                [43 ]Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, Ohio, USA
                [44 ]Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA
                [45 ]Department of Epidemiology, Harvard T.HChan School of Public Health, Boston, Massachusetts, USA
                [46 ]Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, the Hague, the Netherlands
                [47 ]Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
                [48 ]Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere
                [49 ]Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, Tampere, Finland
                [50 ]Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
                [51 ]Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
                [52 ]Institute of Molecular Genetics, National Research Council of Italy, Sassari, Italy
                [53 ]Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, Trieste, Italy
                [54 ]Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, Indiana, USA
                [55 ]Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
                [56 ]Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
                [57 ]Department of Ophthalmology, Flinders University, Adelaide, Australia
                [58 ]Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
                [59 ]Great Ormond Street Institute of Child Health, University College London, London, UK
                [60 ]Ulverscroft Vision Research Group, University College London, London, UK
                [61 ]Université de Bordeaux, Inserm, Bordeaux Population Health Research Center, team LEHA, UMR 1219, F-33000 Bordeaux, France
                [62 ]Institut Pasteur de Lille, Lille, France
                [63 ]Inserm, U1167, RID-AGE - Risk factors and molecular determinants of aging-related diseases, Lille, France
                [64 ]Université de Lille, U1167 - Excellence Laboratory LabEx DISTALZ, Lille, France
                [65 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany
                [66 ]Department of Ophthalmology, Academic Medical Center, Amsterdam, The Netherlands
                [67 ]The Netherlands Institute for Neurosciences (NIN-KNAW), Amsterdam, The Netherlands
                [68 ]Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
                [69 ]Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
                [70 ]Academic Medicine Research Institute, Singapore
                [71 ]Retino Center, Singapore National Eye Centre, Singapore, Singapore
                [72 ]Department of Ophthalmology, Menzies Institute of Medical Research, University of Tasmania, Hobart, Australia
                [73 ]Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia
                [74 ]Department of Genetics, Genomics and Informatics, University of Tennessee Health Sciences Center, Memphis, Tenessee
                [75 ]Department of Ophthalmology, Central Hospital of Central Finland, Jyväskylä, Finland
                [76 ]Gerontology Research Center, Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
                [77 ]Myopia Research Group, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
                [78 ]Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands
                Author notes
                Corresponding author: Prof. dr. Caroline C.W. Klaver, Erasmus Medical Center, room Na-2808, PO Box 2040, 3000 CA, Rotterdam, the Netherlands, c.c.w.klaver@ 123456erasmusmc.nl , phone number +31651934491, fax number +31107044657
                [79]

                These authors contributed equally to this work.

                [80]

                These authors jointly directed this work.

                [#]

                A full list of CREAM consortium members appears at the end of the paper.

                [*]

                Members of the 23andMe Research Team: Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, David A. Hinds, Jennifer C. McCreight, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Vladimir Vacic, Catherine H. Wilson.

                The CREAM Consortium

                Tin Aung 1,2, Joan E. Bailey-Wilson 3, Paul Nigel Baird 4, Amutha Barathi Veluchamy 1,5, Ginevra Biino 6, Kathryn P. Burdon 7, Harry Campbell 8, Li Jia Chen 9, Peng Chen 2, Wei Chen 10, Ching-Yu Cheng 11,12, Emily Chew 13, Jamie E. Craig 7, Phillippa M. Cumberland 14, Margaret M. Deangelis 15, Cécile Delcourt 16, Xiaohu Ding 17, Angela Döring 18, Cornelia M. van Duijn 19, David M. Evans 20,21, Qiao Fan 12, Lindsay Farrer 15, Sheng Feng 22, Brian Fleck 23, Rhys D. Fogarty 7, Jeremy R. Fondran 24, Maurizio Fossarello 25, Paul J. Foster 26, Puya Gharahkhani 27, Christian Gieger 18, Adriana I. Iglesias 19,28,29, Jeremy A. Guggenheim 30, Xiaobo Guo 17,31, Toomas Haller 32, Christopher J. Hammond 33, Caroline Hayward 34, Mingguang He 4,17, Alex W. Hewitt 4,35,36, René Höhn 37,38, S. Mohsen Hosseini 39, Laura D. Howe 21,40, Pirro G. Hysi 33, Robert P. Igo Jr. 24, Sudha K. Iyengar 13,24,41, Sarayut Janmahasatian 24, Vishal Jhanji 9, Jost B. Jonas 42,43, Mika Kähönen 44, Jaakko Kaprio 45,46, John P. Kemp 21, Kay-Tee Khaw 47, Anthony P. Khawaja 26,47, Chiea-Chuen Khor 2,15,48,49, Caroline C. W. Klaver 19,29,50, Barbara E. Klein 51, Ronald Klein 51, Eva Krapohl 52, Jean-François Korobelnik 53,54, Jonathan H. Lass 24,41, Kris Lee 51, Elisabeth M. van Leeuwen 19,29, Terho Lehtimäki 55,56, Shi-Ming Li 43, Yi Lu 27, Robert N. Luben 47, Stuart MacGregor 27, David A. Mackey 4,35,36, Kari-Matti Mäkelä 55, Nicholas G. Martin 57, George McMahon 21, Akira Meguro 58, Thomas Meitinger 59,60, Andres Metspalu 32, Evelin Mihailov 32, Paul Mitchell 61, Masahiro Miyake 62, Nobuhisa Mizuki 58, Margaux Morrison 15, Vinay Nangia 63, Songhomitra Panda-Jonas 63, Chi Pui Pang 9, Olavi Pärssinen 64,65, Andrew D. Paterson 39, Norbert Pfeiffer 38, Mario Pirastu 66, Robert Plomin 52, Ozren Polasek 8,67, Jugnoo S. Rahi 14,26,68, Olli Raitakari 69,70, Taina Rantanen 65, Janina S. Ried 18, Igor Rudan 8, Seang-Mei Saw 48,71, Maria Schache 4, Ilkka Seppälä 55, Rupal L. Shah 30, George Davey Smith 21, Dwight Stambolian 72, Beate St Pourcain 21,73, Claire L. Simpson 3,74, E-Shyong Tai 48, Pancy O. Tam 9, Milly S. Tedja 19,29, Yik-Ying Teo 48,75, J. Willem L. Tideman 19,29, Nicholas J. Timpson 21, Simona Vaccargiu 66, Zoran Vatavuk 76, Virginie J.M. Verhoeven 19,28,29, Veronique Vitart 34, Jie Jin Wang 4,61, Ningli Wang 43, Nick J. Wareham 77, Juho Wedenoja 45,78, Cathy Williams 79, Katie M. Williams 33, James F. Wilson 8,34, Robert Wojciechowski 3,80,81, Ya Xing Wang 43, Tien-Yin Wong 82,83, Alan F. Wright 34, Jing Xie 4, Liang Xu 43, Kenji Yamashiro 62, Maurice K.H. Yap 84, Seyhan Yazar 36, Shea Ping Yip 85, Nagahisa Yoshimura 62, Alvin L. Young 9, Terri L. Young 51, Jing Hua Zhao 77, Wanting Zhao 12,86, Xiangtian Zhou 10

                Affiliations

                1. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

                2. Department of Ophthalmology, National University Health Systems, National University of Singapore, Singapore.

                3. Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

                4. Centre for Eye Research Australia, Ophthalmology, Department of Surgery, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia.

                5. Duke-NUS Medical School, Singapore, Singapore.

                6. Institute of Molecular Genetics, National Research Council of Italy, Sassari, Italy.

                7. Department of Ophthalmology, Flinders University, Adelaide, Australia.

                8. Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

                9. Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, Kowloon, Hong Kong.

                10. School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, China.

                11. Ocular Epidemiology Research Group, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

                12. Centre for Quantitative Medicine, DUKE-National University of Singapore, Singapore.

                13. Department of Genetics, Case Western Reserve University, Cleveland, Ohio, USA.

                14. Great Ormond Street Institute of Child Health, University College London, London, UK.

                15. Department of Ophthalmology and Visual Sciences, John Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.

                16. Université de Bordeaux, Inserm, Bordeaux Population Health Research Center, team LEHA, UMR 1219, F-33000 Bordeaux, France.

                17. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.

                18. Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg, Germany.

                19. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

                20. Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, Queensland, Australia.

                21. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

                22. Department of Pediatric Ophthalmology, Duke Eye Center For Human Genetics, Durham, North Carolina, USA.

                23. Princess Alexandra Eye Pavilion, Edinburgh, UK.

                24. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.

                25. University Hospital ‘San Giovanni di Dio’, Cagliari, Italy.

                26. NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK.

                27. Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

                28. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.

                29. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.

                30. School of Optometry & Vision Sciences, Cardiff University, Cardiff, UK.

                31. Department of Statistical Science, School of Mathematics, Sun Yat-Sen University, Guangzhou, China.

                32. Estonian Genome Center, University of Tartu, Tartu, Estonia.

                33. Section of Academic Ophthalmology, School of Life Course Sciences, King’s College London, London, UK.

                34. MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, UK.

                35. Department of Ophthalmology, Menzies Institute of Medical Research, University of Tasmania, Hobart, Australia.

                36. Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia.

                37. Department of Ophthalmology, University Hospital Bern, Inselspital, University of Bern, Bern, Switzerland.

                38. Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.

                39. Program in Genetics and Genome Biology, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.

                40. School of Social and Community Medicine, University of Bristol, Bristol, UK.

                41. Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, Ohio, USA.

                42. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.

                43. Beijing Institute of Ophthalmology, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

                44. Department of Clinical Physiology, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland.

                45. Department of Public Health, University of Helsinki, Helsinki, Finland.

                46. Institute for Molecular Medicine Finland FIMM, HiLIFE Unit, University of Helsinki, Helsinki, Finland.

                47. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

                48. Saw Swee Hock School of Public Health, National University Health Systems, National University of Singapore, Singapore.

                49. Division of Human Genetics, Genome Institute of Singapore, Singapore.

                50. Department of Ophthalmology, Radboud University Medical Center, Nijmegen, The Netherlands.

                51. Department of Ophthalmology and Visual Sciences, University of Wisconsin–Madison, Madison, Wisconsin, USA.

                52. MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK.

                53. Université de Bordeaux, Bordeaux, France.

                54. INSERM (Institut National de la Santé Et de la Recherche Médicale), ISPED (Institut de Santé Publique d’Épidémiologie et de Développement), Centre INSERM U897-Epidemiologie-Biostatistique, Bordeaux, France.

                55. Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere.

                56. Department of Clinical Chemistry, Fimlab Laboratories, University of Tampere, Tampere, Finland.

                57. Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

                58. Department of Ophthalmology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.

                59. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.

                60. Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.

                61. Department of Ophthalmology, Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia.

                62. Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

                63. Suraj Eye Institute, Nagpur, Maharashtra, India.

                64. Department of Ophthalmology, Central Hospital of Central Finland, Jyväskylä, Finland.

                65. Gerontology Research Center, Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.

                66. Institute of Genetic and Biomedic Research, National Research Council, Cagliari, Italy.

                67. Faculty of Medicine, University of Split, Split, Croatia.

                68. Ulverscroft Vision Research Group, University College London, London, UK.

                69. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.

                70. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.

                71. Myopia Research Group, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

                72. Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

                73. Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.

                74. Department of Genetics, Genomics and Informatics, University of Tennessee Health Sciences Center, Memphis, Tenessee.

                75. Department of Statistics and Applied Probability, National University of Singapore, Singapore.

                76. Department of Ophthalmology, Sisters of Mercy University Hospital, Zagreb, Croatia.

                77. MRC Epidemiology Unit, Institute of Metabolic Sciences, University of Cambridge, Cambridge, UK.

                78. Department of Ophthalmology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

                79. Department of Population Health Sciences, Bristol Medical School, Bristol, UK.

                80. Department of Epidemiology and Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

                81. Wilmer Eye Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

                82. Academic Medicine Research Institute, Singapore.

                83. Retino Center, Singapore National Eye Centre, Singapore, Singapore.

                84. Centre for Myopia Research, School of Optometry, The Hong Kong Polytechnic University, Hong Kong, Hong Kong.

                85. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong, Hong Kong.

                86. Statistics Support Platform, Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

                Article
                NIHMS954993
                10.1038/s41588-018-0127-7
                5980758
                29808027

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