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Nat Genet. 2016 Feb;48(2):134-43. doi: 10.1038/ng.3448. Epub 2015 Dec 21.

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

Fritsche LG1, Igl W2, Bailey JN3, Grassmann F4, Sengupta S1, Bragg-Gresham JL1,5, Burdon KP6, Hebbring SJ7, Wen C8, Gorski M2, Kim IK9, Cho D10, Zack D11,12,13,14,15, Souied E16, Scholl HP11,17, Bala E18, Lee KE19, Hunter DJ20,21, Sardell RJ22, Mitchell P23, Merriam JE24, Cipriani V25,26, Hoffman JD27, Schick T28, Lechanteur YT29, Guymer RH30, Johnson MP31, Jiang Y32, Stanton CM33, Buitendijk GH34,35, Zhan X1,36,37, Kwong AM1, Boleda A38, Brooks M38, Gieser L38, Ratnapriya R38, Branham KE39, Foerster JR1, Heckenlively JR39, Othman MI39, Vote BJ6, Liang HH30, Souzeau E40, McAllister IL41, Isaacs T41, Hall J40, Lake S40, Mackey DA6,30,41, Constable IJ41, Craig JE40, Kitchner TE7, Yang Z42,43, Su Z44, Luo H8, Chen D8, Ouyang H8, Flagg K8, Lin D8, Mao G8, Ferreyra H8, Stark K2, von Strachwitz CN45, Wolf A46, Brandl C2,4,47, Rudolph G46, Olden M2, Morrison MA48, Morgan DJ48, Schu M49,50,51,52,53, Ahn J54, Silvestri G55, Tsironi EE56, Park KH57, Farrer LA49,50,51,52,53, Orlin A58, Brucker A59, Li M60, Curcio CA61, Mohand-Saïd S62,63,64,65, Sahel JA25,62,63,64,65,66,67, Audo I62,63,64,68, Benchaboune M65, Cree AJ69, Rennie CA70, Goverdhan SV69, Grunin M71, Hagbi-Levi S71, Campochiaro P11,13, Katsanis N72,73,74, Holz FG17, Blond F62,63,64, Blanché H75, Deleuze JF75,76, Igo RP Jr3, Truitt B3, Peachey NS18,77, Meuer SM19, Myers CE19, Moore EL19, Klein R19, Hauser MA78,79,80, Postel EA78, Courtenay MD22, Schwartz SG81, Kovach JL81, Scott WK22, Liew G23, Tan AG23, Gopinath B23, Merriam JC24, Smith RT24,82, Khan JC41,83,84, Shahid H84,85, Moore AT25,26,86, McGrath JA27, Laux R3, Brantley MA Jr87, Agarwal A87, Ersoy L28, Caramoy A28, Langmann T28, Saksens NT29, de Jong EK29, Hoyng CB29, Cain MS30, Richardson AJ30, Martin TM88, Blangero J31, Weeks DE32,89, Dhillon B90, van Duijn CM35, Doheny KF91, Romm J91, Klaver CC34,35, Hayward C33, Gorin MB92,93, Klein ML88, Baird PN30, den Hollander AI29,94, Fauser S28, Yates JR25,26,84, Allikmets R24,95, Wang JJ23, Schaumberg DA20,96,97, Klein BE19, Hagstrom SA77, Chowers I71, Lotery AJ69, Léveillard T62,63,64, Zhang K8,44, Brilliant MH7, Hewitt AW6,30,41, Swaroop A38, Chew EY98, Pericak-Vance MA22, DeAngelis M48, Stambolian D10, Haines JL3,99, Iyengar SK3, Weber BH4, Abecasis GR1, Heid IM2.

Author information

1
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
2
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
3
Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
4
Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
5
Kidney Epidemiology and Cost Center, Department of Internal Medicine-Nephrology, University of Michigan, Ann Arbor, Michigan, USA.
6
School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
7
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.
8
Department of Ophthalmology, University of California, San Diego and Veterans Affairs San Diego Health System, La Jolla, California, USA.
9
Retina Service, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.
10
Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
11
Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
12
Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
13
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
14
Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
15
Institue de la Vision, Université Pierre et Marie Curie, Paris, France.
16
Hôpital Intercommunal de Créteil, Hôpital Henri Mondor, Université Paris Est Créteil, Créteil, France.
17
Department of Ophthalmology, University of Bonn, Bonn, Germany.
18
Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.
19
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA.
20
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
21
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
22
John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA.
23
Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
24
Department of Ophthalmology, Columbia University, New York, New York, USA.
25
University College London Institute of Ophthalmology, University College London, London, UK.
26
Moorfields Eye Hospital, London, UK.
27
Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
28
Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
29
Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.
30
Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.
31
South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas, USA.
32
Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
33
Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
34
Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.
35
Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
36
Quantitative Biomedical Research Center, Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
37
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
38
Neurobiology, Neurodegeneration and Repair Laboratory (N-NRL), National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.
39
Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan, USA.
40
Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia.
41
Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia.
42
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.
43
Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China.
44
Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
45
EyeCentre Southwest, Stuttgart, Germany.
46
University Eye Clinic, Ludwig Maximilians University, Munich, Germany.
47
Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany.
48
Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, USA.
49
Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.
50
Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.
51
Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.
52
Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.
53
Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.
54
Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
55
Centre for Experimental Medicine, Queen's University, Belfast, UK.
56
Department of Ophthalmology, University of Thessaly, School of Medicine, Larissa, Greece.
57
Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
58
Department of Ophthalmology, Weill Cornell Medical College, New York, New York, USA.
59
Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
60
Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
61
Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
62
INSERM, Paris, France.
63
Institut de la Vision, Department of Genetics, Paris, France.
64
Centre National de la Recherche Scientifique (CNRS), Paris, France.
65
Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France.
66
Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.
67
Académie des Sciences-Institut de France, Paris, France.
68
Department of Molecular Genetics, Institute of Ophthalmology, London, UK.
69
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
70
University Hospital Southampton, Southampton, UK.
71
Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
72
Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.
73
Department of Cell Biology, Duke University, Durham, North Carolina, USA.
74
Department of Pediatrics, Duke University, Durham, North Carolina, USA.
75
Centre d'Etude du Polymorphisme Humain (CEPH) Fondation Jean Dausset, Paris, France.
76
Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Institut de Génomique, Centre National de Génotypage, Evry, France.
77
Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA.
78
Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA.
79
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
80
Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA.
81
Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Naples, Florida, USA.
82
Department of Ophthalmology, New York University School of Medicine, New York, New York, USA.
83
Department of Ophthalmology, Royal Perth Hospital, Perth, Western Australia, Australia.
84
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
85
Department of Ophthalmology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
86
Department of Ophthalmology, University of California San Francisco Medical School, San Francisco, California, USA.
87
Department of Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, Tennessee, USA.
88
Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA.
89
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
90
School of Clinical Sciences, University of Edinburgh, Edinburgh, UK.
91
Center for Inherited Disease Research (CIDR) Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
92
Department of Ophthalmology, David Geffen School of Medicine, Stein Eye Institute, University of California, Los Angeles, Los Angeles, California, USA.
93
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
94
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
95
Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
96
Center for Translational Medicine, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, USA.
97
Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
98
Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.
99
Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Abstract

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

PMID:
26691988
PMCID:
PMC4745342
DOI:
10.1038/ng.3448
[Indexed for MEDLINE]
Free PMC Article

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