Abstract

Genome-wide association studies (GWAS) for late stage age-related macular degeneration (AMD) have identified 52 independent genetic variants with genome-wide significance at 34 genomic loci. Typically, such an approach rarely results in the identification of functional variants implicating a defined gene in the disease process. We now performed a transcriptome-wide association study (TWAS) allowing the prediction of effects of AMD-associated genetic variants on gene expression. The TWAS was based on the genotypes of 16,144 late-stage AMD cases and 17,832 healthy controls, and gene expression was imputed for 27 different human tissues which were obtained from 134 to 421 individuals. A linear regression model including each individuals imputed gene expression data and the respective AMD status identified 106 genes significantly associated to AMD variants in at least one tissue (Q-value < 0.001). Gene enrichment analysis highlighted rather systemic than tissue- or cell-specific processes. Remarkably, 31 of the 106 genes overlapped with significant GWAS signals of other complex traits and diseases, such as neurological or autoimmune conditions. Taken together, our study highlights the fact that expression of genes associated with AMD is not restricted to retinal tissue as could be expected for an eye disease of the posterior pole, but instead is rather ubiquitous suggesting processes underlying AMD pathology to be of systemic nature.

Details

Title
A transcriptome-wide association study based on 27 tissues identifies 106 genes potentially relevant for disease pathology in age-related macular degeneration
Author
Strunz, Tobias 1 ; Lauwen Susette 2 ; Kiel, Christina 1 ; Fritsche, Lars G 3 ; Igl Wilmar 4 ; Bailey Jessica N Cooke 5 ; Grassmann Felix 1 ; Sengupta Sebanti 3 ; Bragg-Gresham, Jennifer L 6 ; Burdon, Kathryn P 7 ; Hebbring, Scott J 8 ; Wen, Cindy 9 ; Gorski, Mathias 4 ; Kim, Ivana K 10 ; Cho, David 11 ; Zack, Donald 12 ; Souied Eric 13 ; Scholl Hendrik P N 14 ; Bala, Elisa 15 ; Lee, Kristine E 16 ; Hunter, David J 17 ; Sardell, Rebecca J 18 ; Mitchell, Paul 19 ; Merriam, Joanna E 20 ; Cipriani Valentina 21 ; Hoffman, Joshua D 22 ; Schick, Tina 23 ; Lechanteur Yara T E 24 ; Guymer, Robyn H 25 ; Johnson, Matthew P 26 ; Jiang Yingda 27 ; Stanton, Chloe M 28 ; Buitendijk Gabriëlle H S 29 ; Zhan Xiaowei 30 ; Kwong, Alan M 3 ; Boleda Alexis 31 ; Brooks, Matthew 32 ; Gieser Linn 31 ; Rinki, Ratnapriya 31 ; Branham, Kari E 32 ; Foerster, Johanna R 3 ; Heckenlively, John R 32 ; Othman, Mohammad I 32 ; Vote, Brendan J 7 ; Liang, Helena Hai 25 ; Souzeau Emmanuelle 33 ; McAllister, Ian L 34 ; Isaacs, Timothy 34 ; Hall, Janette 33 ; Lake, Stewart 33 ; Mackey, David A 35 ; Constable, Ian J 36 ; Craig, Jamie E 33 ; Kitchner, Terrie E 8 ; Yang Zhenglin 37 ; Su Zhiguang 38 ; Luo Hongrong 39 ; Chen, Daniel 9 ; Ouyang, Hong 9 ; Flagg, Ken 9 ; Lin, Danni 9 ; Mao Guanping 9 ; Ferreyra, Henry 9 ; Stark, Klaus 4 ; Strachwitz Claudia N von 40 ; Wolf, Armin 41 ; Brandl, Caroline 42 ; Guenther, Rudolph 41 ; Olden Matthias 4 ; Morrison, Margaux A 43 ; Morgan, Denise J 43 ; Schu, Matthew 44 ; Ahn Jeeyun 45 ; Silvestri Giuliana 46 ; Tsironi, Evangelia E 47 ; Park, Kyu Hyung 48 ; Farrer, Lindsay A 44 ; Orlin Anton 49 ; Brucker, Alexander 50 ; Li, Mingyao 51 ; Curcio, Christine 52 ; Mohand-Saïd Saddek 53 ; José-Alain, Sahel 54 ; Audo Isabelle 55 ; Benchaboune Mustapha 56 ; Cree, Angela J 57 ; Rennie, Christina A 58 ; Goverdhan Srinivas V 57 ; Grunin Michelle 59 ; Hagbi-Levi Shira 59 ; Campochiaro, Peter 60 ; Katsanis, Nicholas 61 ; Holz, Frank G 62 ; Blond Frédéric 63 ; Blanché Hélène 64 ; Deleuze Jean-François 65 ; Igo, Robert P, Jr 5 ; Truitt, Barbara 5 ; Peachey, Neal S 66 ; Meuer, Stacy M 16 ; Myers, Chelsea E 16 ; Moore, Emily L 16 ; Klein, Ronald 16 ; Hauser, Michael A 67 ; Postel, Eric A 68 ; Courtenay, Monique D 18 ; Schwartz, Stephen G 69 ; Kovach, Jaclyn L 69 ; Scott, William K 18 ; Liew, Gerald 19 ; Tfan, Ava G 19 ; Gopinath Bamini 19 ; Merriam, John C 20 ; Theodore, Smith R 70 ; Khan, Jane C 71 ; Humma, Shahid 72 ; Moore, Anthony T 73 ; Allie, McGrath J 22 ; Laux Reneé 5 ; Brantley, Milam A, Jr 74 ; Agarwal, Anita 74 ; Ersoy Lebriz 23 ; Caramoy Albert 23 ; Langmann, Thomas 23 ; Saksens Nicole T M 24 ; Jong Eiko K de 24 ; Hoyng, Carel B 24 ; Cain, Melinda S 25 ; Richardson, Andrea J 25 ; Martin, Tammy M 75 ; Blangero, John 26 ; Weeks, Daniel E 76 ; Dhillon Bal 77 ; Duijn Cornelia M van 78 ; Doheny, Kimberly F 79 ; Romm, Jane 79 ; Klaver Caroline C W 29 ; Hayward, Caroline 28 ; Gorin, Michael B 80 ; Klein, Michael L 75 ; Baird, Paul N 25 ; Hollander Anneke I den 81 ; Fauser Sascha 23 ; Yates John R W 82 ; Rando, Allikmets 83 ; Wang, Jie Jin 19 ; Schaumberg, Debra A 84 ; Klein Barbara E K 16 ; Hagstrom, Stephanie A 85 ; Chowers Itay 59 ; Lotery Andrew J 57 ; Léveillard Thierry 63 ; Zhang, Kang 39 ; Brilliant, Murray H 8 ; Hewitt, Alex W 35 ; Swaroop Anand 31 ; Chew, Emily Y 86 ; Pericak-Vance, Margaret A 18 ; DeAngelis, Margaret 43 ; Stambolian Dwight 11 ; Haines, Jonathan L 87 ; Iyengar, Sudha K 5 ; Weber Bernhard H F 1 ; Abecasis, Gonçalo R 3 ; Heid, Iris M 4 ; Hollander, Anneke den 2 

1  Institute of Human Genetics, University of Regensburg, Regensburg, Germany (GRID:grid.7727.5) (ISNI:0000 0001 2190 5763) 
2  Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Department of Ophthalmology, Nijmegen, The Netherlands (GRID:grid.7727.5); Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands (GRID:grid.7727.5) 
3  University of Michigan, Center for Statistical Genetics, Department of Biostatistics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
4  University of Regensburg, Department of Genetic Epidemiology, Regensburg, Germany (GRID:grid.7727.5) (ISNI:0000 0001 2190 5763) 
5  Case Western Reserve University School of Medicine, Department of Epidemiology and Biostatistics, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847) 
6  University of Michigan, Center for Statistical Genetics, Department of Biostatistics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); Kidney Epidemiology and Cost Center, Department of Biostatistics, Department of Internal Medicine - Nephrology, University of Michigan, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
7  School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia (GRID:grid.1009.8) (ISNI:0000 0004 1936 826X) 
8  Center for Human Genetics, Marshfield Clinic Research Foundation, 1000N. Oak Ave, Marshfield, USA (GRID:grid.280718.4) (ISNI:0000 0000 9274 7048) 
9  Department of Ophthalmology, University of California San Diego and VA San Diego Health System, La Jolla, California, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
10  Retina Service, Massachusetts Eye and Ear, Department of Ophthalmology Harvard Medical School, Boston, USA (GRID:grid.39479.30) (ISNI:0000 0000 8800 3003) 
11  Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
12  Department of Ophthalmology, Wilmer Eye Institute - Johns Hopkins University School of Medicine - 400 North Broadway, Smith Building -, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Department of Molecular Biology and Genetics - Johns Hopkins University School of Medicine - 400 North Broadway, Smith Building -, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Department of Neuroscience - Johns Hopkins University School of Medicine - 400 North Broadway, Smith Building -, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Institute of Genetic Medicine - Johns Hopkins University School of Medicine - 400 North Broadway, Smith Building -, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Institue de la Vision, Université Pierre et Marie Curie, 17 rue Moreau, Paris, France (GRID:grid.462844.8) (ISNI:0000 0001 2308 1657) 
13  Hôpital Intercommunal de Créteil, Hôpital Henri Mondor - Université Paris Est Créteil, Créteil, France (GRID:grid.414145.1) (ISNI:0000 0004 1765 2136) 
14  Department of Ophthalmology, Wilmer Eye Institute - Johns Hopkins University School of Medicine - 400 North Broadway, Smith Building -, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); University of Bonn - Department of Ophthalmology - Ernst-Abbe-Str. 2, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300) 
15  Louis Stokes Cleveland VA Medical Center, 10701 East Boulevard, Cleveland, USA (GRID:grid.410349.b) (ISNI:0000 0004 0420 190X) 
16  Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, USA (GRID:grid.14003.36) (ISNI:0000 0001 2167 3675) 
17  Department of Epidemiology, Harvard School of Public Health, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Department of Nutrition, Harvard School of Public Health, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
18  John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, United States (GRID:grid.26790.3a) (ISNI:0000 0004 1936 8606) 
19  Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, Australia (GRID:grid.1013.3) (ISNI:0000 0004 1936 834X) 
20  Department of Ophthalmology Columbia University, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
21  UCL Institute of Ophthalmology, University College London, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Moorfields Eye Hospital, London, UK (GRID:grid.439257.e) (ISNI:0000 0000 8726 5837) 
22  Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, United States (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
23  University Hospital of Cologne, Department of Ophthalmology, Kerpener Str. 62, Cologne, Germany (GRID:grid.411097.a) (ISNI:0000 0000 8852 305X) 
24  Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
25  Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
26  South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, USA (GRID:grid.449717.8) (ISNI:0000 0004 5374 269X) 
27  Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
28  MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
29  Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X); Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
30  University of Michigan, Center for Statistical Genetics, Department of Biostatistics, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); Quantitative Biomedical Research Center, Department of Clinical Science, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121); Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121) 
31  Neurobiology Neurodegeneration & Repair Laboratory (N-NRL), National Eye Institute, National Institutes of Health, Bethesda, USA (GRID:grid.280030.9) (ISNI:0000 0001 2150 6316) 
32  Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370) 
33  Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, Australia (GRID:grid.1014.4) (ISNI:0000 0004 0367 2697) 
34  Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia (GRID:grid.1014.4) 
35  School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Australia (GRID:grid.1009.8) (ISNI:0000 0004 1936 826X); Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia (GRID:grid.1008.9) 
36  Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia (GRID:grid.1008.9) 
37  Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People’s Hospital, Chengdu, China (GRID:grid.410646.1) (ISNI:0000 0004 1808 0950); Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China (GRID:grid.9227.e) (ISNI:0000000119573309) 
38  Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan, China (GRID:grid.9227.e) 
39  Department of Ophthalmology, University of California San Diego and VA San Diego Health System, La Jolla, California, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan, China (GRID:grid.266100.3) 
40  EyeCentre Southwest Stuttgart, Stuttgart, Germany (GRID:grid.7727.5) 
41  University Eye Clinic, Ludwig-Maximilians-University Munich, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
42  University of Regensburg, Department of Genetic Epidemiology, Regensburg, Germany (GRID:grid.7727.5) (ISNI:0000 0001 2190 5763); Institute of Human Genetics, University of Regensburg, Regensburg, Germany (GRID:grid.7727.5) (ISNI:0000 0001 2190 5763); Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany (GRID:grid.411941.8) (ISNI:0000 0000 9194 7179) 
43  Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096) 
44  Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558); Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, USA (GRID:grid.189504.1) (ISNI:0000 0004 1936 7558) 
45  Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea (GRID:grid.412479.d) 
46  Centre for Experimental Medicine, Queen’s University, Belfast, UK (GRID:grid.4777.3) (ISNI:0000 0004 0374 7521) 
47  Department of Ophthalmology, University of Thessaly, School of Medicine, Larissa, Greece (GRID:grid.410558.d) (ISNI:0000 0001 0035 6670) 
48  Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea (GRID:grid.412480.b) (ISNI:0000 0004 0647 3378) 
49  Department of Ophthalmology, Weill Cornell Medical College, New York, USA (GRID:grid.5386.8) (ISNI:000000041936877X) 
50  Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
51  Department of Biostatistics and Epidemiology University of Pennsylvania Perelman School of Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
52  Department of Ophthalmology, The University of Alabama at Birmingham 1670 University Boulevard VH 360, Birmingham, UK (GRID:grid.25879.31) 
53  INSERM, U968, Paris, France (GRID:grid.7429.8) (ISNI:0000000121866389); UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Department of Genetics, Paris, France (GRID:grid.462844.8) (ISNI:0000 0001 2308 1657); CNRS, UMR_7210, Paris, France (GRID:grid.4444.0) (ISNI:0000 0001 2112 9282); Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France (GRID:grid.415610.7) (ISNI:0000 0001 0657 9752) 
54  INSERM, U968, Paris, France (GRID:grid.7429.8) (ISNI:0000000121866389); UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Department of Genetics, Paris, France (GRID:grid.462844.8) (ISNI:0000 0001 2308 1657); CNRS, UMR_7210, Paris, France (GRID:grid.4444.0) (ISNI:0000 0001 2112 9282); Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France (GRID:grid.415610.7) (ISNI:0000 0001 0657 9752); Fondation Ophtalmologique Adolphe de Rothschild, Paris, France (GRID:grid.417888.a) (ISNI:0000 0001 2177 525X); Institute of Ophthalmology, University College of London, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Académie des Sciences–Institut de France, Paris, France (GRID:grid.83440.3b) 
55  INSERM, U968, Paris, France (GRID:grid.7429.8) (ISNI:0000000121866389); UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Department of Genetics, Paris, France (GRID:grid.462844.8) (ISNI:0000 0001 2308 1657); CNRS, UMR_7210, Paris, France (GRID:grid.4444.0) (ISNI:0000 0001 2112 9282); Department of Molecular Genetics, Institute of Ophthalmology, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
56  Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France (GRID:grid.415610.7) (ISNI:0000 0001 0657 9752) 
57  Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK (GRID:grid.5491.9) (ISNI:0000 0004 1936 9297) 
58  University Hospital Southampton, Southampton, UK (GRID:grid.123047.3) (ISNI:0000000103590315) 
59  Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (GRID:grid.17788.31) (ISNI:0000 0001 2221 2926) 
60  Department of Ophthalmology, Wilmer Eye Institute - Johns Hopkins University School of Medicine - 400 North Broadway, Smith Building -, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Department of Neuroscience - Johns Hopkins University School of Medicine - 400 North Broadway, Smith Building -, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
61  Center for Human Disease Modeling, Duke University, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961); Department of Cell Biology, Duke University, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961); Department of Pediatrics, Duke University, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
62  University of Bonn - Department of Ophthalmology - Ernst-Abbe-Str. 2, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300) 
63  INSERM, U968, Paris, France (GRID:grid.7429.8) (ISNI:0000000121866389); UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Department of Genetics, Paris, France (GRID:grid.462844.8) (ISNI:0000 0001 2308 1657); CNRS, UMR_7210, Paris, France (GRID:grid.4444.0) (ISNI:0000 0001 2112 9282) 
64  CEPH Fondation Jean Dausset 27 rue Juliette Dodu, Paris, France (GRID:grid.4444.0) 
65  CEPH Fondation Jean Dausset 27 rue Juliette Dodu, Paris, France (GRID:grid.4444.0); CEA – IG – Centre National de Génotypage 2 rue Gaston Crémieux, Evry Cédex, France (GRID:grid.4444.0) 
66  Louis Stokes Cleveland VA Medical Center, 10701 East Boulevard, Cleveland, USA (GRID:grid.410349.b) (ISNI:0000 0004 0420 190X); Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725) 
67  Department of Ophthalmology, Duke University Medical Center, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216); Department of Medicine, Duke University Medical Center, Durham, USA (GRID:grid.414179.e) (ISNI:0000 0001 2232 0951); Duke Molecular Physiology Institute, Duke University Medical Center, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
68  Department of Ophthalmology, Duke University Medical Center, Durham, USA (GRID:grid.189509.c) (ISNI:0000000100241216) 
69  Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, 3880 Tamiami Trail North, Naples, USA (GRID:grid.26790.3a) 
70  Department of Ophthalmology Columbia University, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729); Department of Ophthalmology, NYU School of Medicine, New York, USA (GRID:grid.137628.9) (ISNI:0000 0004 1936 8753) 
71  Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Australia (GRID:grid.137628.9); Department of Ophthalmology, Royal Perth Hospital, Perth, Australia (GRID:grid.416195.e) (ISNI:0000 0004 0453 3875); Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
72  Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Department of Ophthalmology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK (GRID:grid.24029.3d) (ISNI:0000 0004 0383 8386) 
73  UCL Institute of Ophthalmology, University College London, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Moorfields Eye Hospital, London, UK (GRID:grid.439257.e) (ISNI:0000 0000 8726 5837); Department of Ophthalmology UCSF Medical School, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
74  Department of Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, United States (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217) 
75  Casey Eye Institute, Oregon Health & Science University, Portland, USA (GRID:grid.5288.7) (ISNI:0000 0000 9758 5690) 
76  Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000); Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, USA (GRID:grid.21925.3d) (ISNI:0000 0004 1936 9000) 
77  School of Clinical Sciences University of Edinburgh, Scotland, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
78  Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
79  Center for Inherited Disease Research (CIDR) Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
80  Department of Ophthalmology, David Geffen School of Medicine—UCLA, Stein Eye Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); Department of Human Genetics, David Geffen School of Medicine—UCLA, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
81  Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
82  UCL Institute of Ophthalmology, University College London, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); Moorfields Eye Hospital, London, UK (GRID:grid.439257.e) (ISNI:0000 0000 8726 5837); Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
83  Department of Ophthalmology Columbia University, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729); Department of Pathology & Cell Biology, Columbia University, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
84  Department of Epidemiology, Harvard School of Public Health, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X); Center for Translational Medicine, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096); Division of Preventive Medicine, Brigham & Women’s Hospital, Harvard Medical School, Boston, USA (GRID:grid.223827.e) 
85  Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, USA (GRID:grid.239578.2) (ISNI:0000 0001 0675 4725) 
86  Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, National Institutes of Health, Bethesda, USA (GRID:grid.280030.9) (ISNI:0000 0001 2150 6316) 
87  Case Western Reserve University School of Medicine, Department of Epidemiology and Biostatistics, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847); Institute for Computational Biology, Case Western Reserve University School of Medicine, 2103 Cornell Rd, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-020-58510-9
ProQuest document ID
2349174811
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.