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

Lars G Fritsche¹, Wilmar Igl², Jessica N Cooke Bailey³, Felix Grassmann⁴, Sebanti Sengupta¹, Jennifer L Bragg-Gresham^{1

5}, Kathryn P Burdon⁶, Scott J Hebbring⁷, Cindy Wen⁸, Mathias Gorski², Ivana K Kim⁹, David Cho¹⁰, Donald Zack^{11

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15}, Eric Souied¹⁶, Hendrik P N Scholl^{11

17}, Elisa Bala¹⁸, Kristine E Lee¹⁹, David J Hunter^{20

21}, Rebecca J Sardell²², Paul Mitchell²³, Joanna E Merriam²⁴, Valentina Cipriani^{25

26}, Joshua D Hoffman²⁷, Tina Schick²⁸, Yara T E Lechanteur²⁹, Robyn H Guymer³⁰, Matthew P Johnson³¹, Yingda Jiang³², Chloe M Stanton³³, Gabriëlle H S Buitendijk^{34

35}, Xiaowei Zhan^{1

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37}, Alan M Kwong¹, Alexis Boleda³⁸, Matthew Brooks³⁸, Linn Gieser³⁸, Rinki Ratnapriya³⁸, Kari E Branham³⁹, Johanna R Foerster¹, John R Heckenlively³⁹, Mohammad I Othman³⁹, Brendan J Vote⁶, Helena Hai Liang³⁰, Emmanuelle Souzeau⁴⁰, Ian L McAllister⁴¹, Timothy Isaacs⁴¹, Janette Hall⁴⁰, Stewart Lake⁴⁰, David A Mackey^{6

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41}, Ian J Constable⁴¹, Jamie E Craig⁴⁰, Terrie E Kitchner⁷, Zhenglin Yang^{42

43}, Zhiguang Su⁴⁴, Hongrong Luo⁸, Daniel Chen⁸, Hong Ouyang⁸, Ken Flagg⁸, Danni Lin⁸, Guanping Mao⁸, Henry Ferreyra⁸, Klaus Stark², Claudia N von Strachwitz⁴⁵, Armin Wolf⁴⁶, Caroline Brandl^{2

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47}, Guenther Rudolph⁴⁶, Matthias Olden², Margaux A Morrison⁴⁸, Denise J Morgan⁴⁸, Matthew Schu^{49

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53}, Jeeyun Ahn⁵⁴, Giuliana Silvestri⁵⁵, Evangelia E Tsironi⁵⁶, Kyu Hyung Park⁵⁷, Lindsay A Farrer^{49

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53}, Anton Orlin⁵⁸, Alexander Brucker⁵⁹, Mingyao Li⁶⁰, Christine A Curcio⁶¹, Saddek Mohand-Saïd^{62

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65}, José-Alain Sahel^{25

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67}, Isabelle Audo^{62

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68}, Mustapha Benchaboune⁶⁵, Angela J Cree⁶⁹, Christina A Rennie⁷⁰, Srinivas V Goverdhan⁶⁹, Michelle Grunin⁷¹, Shira Hagbi-Levi⁷¹, Peter Campochiaro^{11

13}, Nicholas Katsanis^{72

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74}, Frank G Holz¹⁷, Frédéric Blond^{62

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64}, Hélène Blanché⁷⁵, Jean-François Deleuze^{75

76}, Robert P Igo Jr³, Barbara Truitt³, Neal S Peachey^{18

77}, Stacy M Meuer¹⁹, Chelsea E Myers¹⁹, Emily L Moore¹⁹, Ronald Klein¹⁹, Michael A Hauser^{78

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80}, Eric A Postel⁷⁸, Monique D Courtenay²², Stephen G Schwartz⁸¹, Jaclyn L Kovach⁸¹, William K Scott²², Gerald Liew²³, Ava G Tan²³, Bamini Gopinath²³, John C Merriam²⁴, R Theodore Smith^{24

82}, Jane C Khan^{41

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84}, Humma Shahid^{84

85}, Anthony T Moore^{25

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86}, J Allie McGrath²⁷, Reneé Laux³, Milam A Brantley Jr⁸⁷, Anita Agarwal⁸⁷, Lebriz Ersoy²⁸, Albert Caramoy²⁸, Thomas Langmann²⁸, Nicole T M Saksens²⁹, Eiko K de Jong²⁹, Carel B Hoyng²⁹, Melinda S Cain³⁰, Andrea J Richardson³⁰, Tammy M Martin⁸⁸, John Blangero³¹, Daniel E Weeks^{32

89}, Bal Dhillon⁹⁰, Cornelia M van Duijn³⁵, Kimberly F Doheny⁹¹, Jane Romm⁹¹, Caroline C W Klaver^{34

35}, Caroline Hayward³³, Michael B Gorin^{92

93}, Michael L Klein⁸⁸, Paul N Baird³⁰, Anneke I den Hollander^{29

94}, Sascha Fauser²⁸, John R W Yates^{25

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84}, Rando Allikmets^{24

95}, Jie Jin Wang²³, Debra A Schaumberg^{20

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97}, Barbara E K Klein¹⁹, Stephanie A Hagstrom⁷⁷, Itay Chowers⁷¹, Andrew J Lotery⁶⁹, Thierry Léveillard^{62

63

64}, Kang Zhang^{8

44}, Murray H Brilliant⁷, Alex W Hewitt^{6

30

41}, Anand Swaroop³⁸, Emily Y Chew⁹⁸, Margaret A Pericak-Vance²², Margaret DeAngelis⁴⁸, Dwight Stambolian¹⁰, Jonathan L Haines^{3

99}, Sudha K Iyengar³, Bernhard H F Weber⁴, Gonçalo R Abecasis¹, Iris M Heid²

Affiliations

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.

PMID: 26691988
PMCID: PMC4745342
DOI: 10.1038/ng.3448 (V体育2025版)

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

Lars G Fritsche et al. Nat Genet. 2016 Feb.

. 2016 Feb;48(2):134-43.

doi: 10.1038/ng.3448. Epub 2015 Dec 21.

Authors

Affiliations

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.

PMID: 26691988
PMCID: PMC4745342
DOI: 10.1038/ng.3448

"V体育ios版" 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)) VSports手机版. 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. .

PubMed Disclaimer

Figures (V体育ios版)

**Figure 1. Genome-wide search reveals 34 loci and genes with rare variant burden for AMD**
(a) We conducted a genome-wide single variant association analysis for >12 million variants in 16,144 advanced AMD patients versus 17,832 controls. Shown is the Manhattan Plot exhibiting P-values for association highlighting novel (P < 5×10^–8 for the first time, green) and known (blue) AMD loci (see Table 1). (b) We computed independent effect size (Odds Ratios) of each of the 52 identified variants (Supplementary Table 4). Shown are these effect sizes versus the frequency of the AMD risk increasing allele and a 80% power curve. (c) We conducted a genome-wide gene-based test for disease burden based on the protein-altering variants testing 17,044 RefSeq genes by the variable threshold test. Shown is the Manhattan Plot with P-values, the red horizontal line indicating genome-wide significance (P ≤ 0.05/17,044 = 2.9×10^–6) and the yellow line indicating AMD-locus-wide significance (given 703 genes in the 34 AMD loci, P ≤ 0.05/703 = 7.1×10^–5). No gene outside the 34 loci is genome-wide significant; 14 genes are AMD-locus-wide significant (blue), four remain significant after locus-wide conditioning (bold letters, Supplementary Table 11).

**Figure 2. Genes with top priority based on biological and statistical evidence combined**
We queried 368 genes in the 34 narrow AMD regions (index and proxies, r ≥0.5, ±100kb) for biological (red; expression in retina/RPE/choroid, Supplementary File 6; ocular mouse phenotype, Supplementary File 7), statistical, (blue; ≥1 credible set variant in gene ±50 kb, Supplementary File 3; rare variant burden, Table 2), putative functional (green; ≥ 1 credible set variant in gene ±50 kb being protein-altering, 5′/3′ UTR, other exonic, or putative promoter, Supplementary File 3), and molecular (magenta; enriched molecular pathway, drug target) evidence. We here focus on the gene(s) with the highest gene priority score (GPS) per locus (full list of genes in Supplementary File 9). Shown are **(a)** the 16 genes with highest GPS in the 15 novel AMD loci (one novel locus without any gene), and (b) the 25 genes with highest GPS in the 18 known AMD loci. Colored fields indicate yes and GPS counts number of colored fields per row.

**Figure 3. Comparison of advanced AMD subtypes and intermediate versus advanced AMD**
We compared associations of the 34 lead variants across different AMD phenotypes. Shown are effect sizes (log Odds Ratio) per minor allele in controls as well as 95% confidence intervals (widths and heights of diamonds). (a) Comparison of neovascular disease (10,749 CNV cases vs. 17,832 controls) and GA (3,235 GA cases vs. 17,832 controls) identified four variants (in loci *MMP9*, *ARMS2*/*HTRA1*, *CETP*, and *SYN3*/*TIMP3*) with significantly different association comparing CNV with GA (P_diff < 0.05/34, marked in red, see also Supplementary Table 16). (b) Comparison of intermediate AMD (6,657 cases vs. 17,832 controls) with advanced AMD (16,144 cases vs. 17,832 controls) identifies 24 variants with nominally significant (P < 0.05, marked in red) association with intermediate AMD (P_binomial = 4.8 × 10^–24), all of which have the same effect direction and less extreme effect sizes compared to advanced AMD (Supplementary Table 17).

**Figure 4. Variance explained and absolute risk of disease based on the 52 identified variants**
(a) Absolute disease risk (=proportion of affected) by genetic risk score intervals (deciles and top 10 percentiles in embedded bar plot) based on our cases-control-data weighted to model a general population with 5% disease prevalence (see also Supplementary Table 20). (b) Shown is disease liability explained by the 52 identified variants (bars) compared to the genomic heritability based on all genotyped variants (red lines) assuming disease prevalence of 1%, 5%, or 10%, respectively.

See this image and copyright information in PMC

References

1. Smith W, et al. Risk factors for age-related macular degeneration: Pooled findings from three continents. Ophthalmology. 2001;108:697–704. - PubMed
1. Chakravarthy U, Evans J, Rosenfeld PJ. Age related macular degeneration. BMJ. 2010;340:c981. - PubMed (VSports注册入口)
1. Ferris FL, et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005;123:1570–4. - PMC - PubMed
1. Wong WL, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2:e106–16. - PubMed
1. Fritsche LG, et al. Age-related macular degeneration: genetics and biology coming together. Annu Rev Genomics Hum Genet. 2014;15:151–71. - VSports注册入口 - PMC - PubMed

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

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

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