Article | Published:

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

Nature Genetics volume 48, pages 134143 (2016) | Download Citation

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.

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Acknowledgements

We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H.

Author information

Author notes

    • Lars G Fritsche
    • , Wilmar Igl
    • , Jessica N Cooke Bailey
    • , Felix Grassmann
    •  & Sebanti Sengupta

    These authors contributed equally to this work.

    • Margaret A Pericak-Vance
    • , Margaret DeAngelis
    • , Dwight Stambolian
    • , Jonathan L Haines
    • , Sudha K Iyengar
    • , Bernhard H F Weber
    • , Gonçalo R Abecasis
    •  & Iris M Heid

    These authors jointly supervised this work.

Affiliations

  1. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Lars G Fritsche
    • , Sebanti Sengupta
    • , Jennifer L Bragg-Gresham
    • , Xiaowei Zhan
    • , Alan M Kwong
    • , Johanna R Foerster
    •  & Gonçalo R Abecasis
  2. Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.

    • Wilmar Igl
    • , Mathias Gorski
    • , Klaus Stark
    • , Caroline Brandl
    • , Matthias Olden
    •  & Iris M Heid
  3. Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

    • Jessica N Cooke Bailey
    • , Robert P Igo Jr
    • , Barbara Truitt
    • , Reneé Laux
    • , Jonathan L Haines
    •  & Sudha K Iyengar
  4. Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

    • Felix Grassmann
    • , Caroline Brandl
    •  & Bernhard H F Weber
  5. Kidney Epidemiology and Cost Center, Department of Internal Medicine–Nephrology, University of Michigan, Ann Arbor, Michigan, USA.

    • Jennifer L Bragg-Gresham
  6. School of Medicine, Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.

    • Kathryn P Burdon
    • , Brendan J Vote
    • , David A Mackey
    •  & Alex W Hewitt
  7. Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, Wisconsin, USA.

    • Scott J Hebbring
    • , Terrie E Kitchner
    •  & Murray H Brilliant
  8. Department of Ophthalmology, University of California, San Diego and Veterans Affairs San Diego Health System, La Jolla, California, USA.

    • Cindy Wen
    • , Hongrong Luo
    • , Daniel Chen
    • , Hong Ouyang
    • , Ken Flagg
    • , Danni Lin
    • , Guanping Mao
    • , Henry Ferreyra
    •  & Kang Zhang
  9. Retina Service, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA.

    • Ivana K Kim
  10. Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • David Cho
    •  & Dwight Stambolian
  11. Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Donald Zack
    • , Hendrik P N Scholl
    •  & Peter Campochiaro
  12. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Donald Zack
  13. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Donald Zack
    •  & Peter Campochiaro
  14. Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Donald Zack
  15. Institue de la Vision, Université Pierre et Marie Curie, Paris, France.

    • Donald Zack
  16. Hôpital Intercommunal de Créteil, Hôpital Henri Mondor, Université Paris Est Créteil, Créteil, France.

    • Eric Souied
  17. Department of Ophthalmology, University of Bonn, Bonn, Germany.

    • Hendrik P N Scholl
    •  & Frank G Holz
  18. Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, USA.

    • Elisa Bala
    •  & Neal S Peachey
  19. Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA.

    • Kristine E Lee
    • , Stacy M Meuer
    • , Chelsea E Myers
    • , Emily L Moore
    • , Ronald Klein
    •  & Barbara E K Klein
  20. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • David J Hunter
    •  & Debra A Schaumberg
  21. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • David J Hunter
  22. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, USA.

    • Rebecca J Sardell
    • , Monique D Courtenay
    • , William K Scott
    •  & Margaret A Pericak-Vance
  23. Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.

    • Paul Mitchell
    • , Gerald Liew
    • , Ava G Tan
    • , Bamini Gopinath
    •  & Jie Jin Wang
  24. Department of Ophthalmology, Columbia University, New York, New York, USA.

    • Joanna E Merriam
    • , John C Merriam
    • , R Theodore Smith
    •  & Rando Allikmets
  25. University College London Institute of Ophthalmology, University College London, London, UK.

    • Valentina Cipriani
    • , José-Alain Sahel
    • , Anthony T Moore
    •  & John R W Yates
  26. Moorfields Eye Hospital, London, UK.

    • Valentina Cipriani
    • , Anthony T Moore
    •  & John R W Yates
  27. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Joshua D Hoffman
    •  & J Allie McGrath
  28. Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.

    • Tina Schick
    • , Lebriz Ersoy
    • , Albert Caramoy
    • , Thomas Langmann
    •  & Sascha Fauser
  29. Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.

    • Yara T E Lechanteur
    • , Nicole T M Saksens
    • , Eiko K de Jong
    • , Carel B Hoyng
    •  & Anneke I den Hollander
  30. Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.

    • Robyn H Guymer
    • , Helena Hai Liang
    • , David A Mackey
    • , Melinda S Cain
    • , Andrea J Richardson
    • , Paul N Baird
    •  & Alex W Hewitt
  31. South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, Texas, USA.

    • Matthew P Johnson
    •  & John Blangero
  32. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Yingda Jiang
    •  & Daniel E Weeks
  33. Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Chloe M Stanton
    •  & Caroline Hayward
  34. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Gabriëlle H S Buitendijk
    •  & Caroline C W Klaver
  35. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Gabriëlle H S Buitendijk
    • , Cornelia M van Duijn
    •  & Caroline C W Klaver
  36. Quantitative Biomedical Research Center, Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Xiaowei Zhan
  37. Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Xiaowei Zhan
  38. Neurobiology, Neurodegeneration and Repair Laboratory (N-NRL), National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Alexis Boleda
    • , Matthew Brooks
    • , Linn Gieser
    • , Rinki Ratnapriya
    •  & Anand Swaroop
  39. Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan, USA.

    • Kari E Branham
    • , John R Heckenlively
    •  & Mohammad I Othman
  40. Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia.

    • Emmanuelle Souzeau
    • , Janette Hall
    • , Stewart Lake
    •  & Jamie E Craig
  41. Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia.

    • Ian L McAllister
    • , Timothy Isaacs
    • , David A Mackey
    • , Ian J Constable
    • , Jane C Khan
    •  & Alex W Hewitt
  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.

    • Zhenglin Yang
  43. Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China.

    • Zhenglin Yang
  44. Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

    • Zhiguang Su
    •  & Kang Zhang
  45. EyeCentre Southwest, Stuttgart, Germany.

    • Claudia N von Strachwitz
  46. University Eye Clinic, Ludwig Maximilians University, Munich, Germany.

    • Armin Wolf
    •  & Guenther Rudolph
  47. Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany.

    • Caroline Brandl
  48. Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, Utah, USA.

    • Margaux A Morrison
    • , Denise J Morgan
    •  & Margaret DeAngelis
  49. Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.

    • Matthew Schu
    •  & Lindsay A Farrer
  50. Department of Ophthalmology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.

    • Matthew Schu
    •  & Lindsay A Farrer
  51. Department of Neurology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.

    • Matthew Schu
    •  & Lindsay A Farrer
  52. Department of Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.

    • Matthew Schu
    •  & Lindsay A Farrer
  53. Department of Biostatistics, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.

    • Matthew Schu
    •  & Lindsay A Farrer
  54. Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.

    • Jeeyun Ahn
  55. Centre for Experimental Medicine, Queen's University, Belfast, UK.

    • Giuliana Silvestri
  56. Department of Ophthalmology, University of Thessaly, School of Medicine, Larissa, Greece.

    • Evangelia E Tsironi
  57. Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.

    • Kyu Hyung Park
  58. Department of Ophthalmology, Weill Cornell Medical College, New York, New York, USA.

    • Anton Orlin
  59. Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

    • Alexander Brucker
  60. Department of Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

    • Mingyao Li
  61. Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

    • Christine A Curcio
  62. INSERM, Paris, France.

    • Saddek Mohand-Saïd
    • , José-Alain Sahel
    • , Isabelle Audo
    • , Frédéric Blond
    •  & Thierry Léveillard
  63. Institut de la Vision, Department of Genetics, Paris, France.

    • Saddek Mohand-Saïd
    • , José-Alain Sahel
    • , Isabelle Audo
    • , Frédéric Blond
    •  & Thierry Léveillard
  64. Centre National de la Recherche Scientifique (CNRS), Paris, France.

    • Saddek Mohand-Saïd
    • , José-Alain Sahel
    • , Isabelle Audo
    • , Frédéric Blond
    •  & Thierry Léveillard
  65. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris, France.

    • Saddek Mohand-Saïd
    • , José-Alain Sahel
    •  & Mustapha Benchaboune
  66. Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.

    • José-Alain Sahel
  67. Académie des Sciences–Institut de France, Paris, France.

    • José-Alain Sahel
  68. Department of Molecular Genetics, Institute of Ophthalmology, London, UK.

    • Isabelle Audo
  69. Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

    • Angela J Cree
    • , Srinivas V Goverdhan
    •  & Andrew J Lotery
  70. University Hospital Southampton, Southampton, UK.

    • Christina A Rennie
  71. Department of Ophthalmology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

    • Michelle Grunin
    • , Shira Hagbi-Levi
    •  & Itay Chowers
  72. Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA.

    • Nicholas Katsanis
  73. Department of Cell Biology, Duke University, Durham, North Carolina, USA.

    • Nicholas Katsanis
  74. Department of Pediatrics, Duke University, Durham, North Carolina, USA.

    • Nicholas Katsanis
  75. Centre d’Etude du Polymorphisme Humain (CEPH) Fondation Jean Dausset, Paris, France.

    • Hélène Blanché
    •  & Jean-François Deleuze
  76. Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Institut de Génomique, Centre National de Génotypage, Evry, France.

    • Jean-François Deleuze
  77. Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Neal S Peachey
    •  & Stephanie A Hagstrom
  78. Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA.

    • Michael A Hauser
    •  & Eric A Postel
  79. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • Michael A Hauser
  80. Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, USA.

    • Michael A Hauser
  81. Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Naples, Florida, USA.

    • Stephen G Schwartz
    •  & Jaclyn L Kovach
  82. Department of Ophthalmology, New York University School of Medicine, New York, New York, USA.

    • R Theodore Smith
  83. Department of Ophthalmology, Royal Perth Hospital, Perth, Western Australia, Australia.

    • Jane C Khan
  84. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

    • Jane C Khan
    • , Humma Shahid
    •  & John R W Yates
  85. Department of Ophthalmology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.

    • Humma Shahid
  86. Department of Ophthalmology, University of California San Francisco Medical School, San Francisco, California, USA.

    • Anthony T Moore
  87. Department of Ophthalmology and Visual Sciences, Vanderbilt University, Nashville, Tennessee, USA.

    • Milam A Brantley Jr
    •  & Anita Agarwal
  88. Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, USA.

    • Tammy M Martin
    •  & Michael L Klein
  89. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Daniel E Weeks
  90. School of Clinical Sciences, University of Edinburgh, Edinburgh, UK.

    • Bal Dhillon
  91. Center for Inherited Disease Research (CIDR) Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Kimberly F Doheny
    •  & Jane Romm
  92. Department of Ophthalmology, David Geffen School of Medicine, Stein Eye Institute, University of California, Los Angeles, Los Angeles, California, USA.

    • Michael B Gorin
  93. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Michael B Gorin
  94. Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.

    • Anneke I den Hollander
  95. Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.

    • Rando Allikmets
  96. Center for Translational Medicine, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, USA.

    • Debra A Schaumberg
  97. Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Debra A Schaumberg
  98. Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Emily Y Chew
  99. Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

    • Jonathan L Haines

Authors

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Contributions

Clinical ascertainment, contribution of samples, study coordination and data analysis. G.R.A., A.A., J.A., R.A., I.A., A. Brucker, P.N.B., E.B., M. Benchaboune, H.B., J.B., F.B., A. Boleda, C.B., K.E.B., M.H.B., K.P.B., M.S.C., P.C., A.C., D. Chen, D. Cho, I.C., I.J.C., J.E.C., A.J.C., C.A.C., M.D., J.-F.D., A.I.d.H., B.D., L.E., L.A.F., S.F., H.F., K.F., J.R.F., L.G.F., L.G., B.G., M.B.G., S.V.G., R.H.G., S.H.-L., S.A.H., J.L.H., J.H., M.A.H., C.H., S.J.H., J.R.H., I.M.H., A.W.H., J.D.H., F.G.H., C.B.H., D.J.H., T.I., S.K.I., M.P.J., N.K., J.C.K., I.K.K., T.E.K., C.C.W.K., B.E.K.K., M.L.K., R.K., J.L.K., A.M.K., S.L., T. Langmann, R.L., Y.T.E.L., K.E.L., T. Léveillard, M.L., H.H.L., G.L., D.L., A.J.L., H.L., D.A.M., G.M., T.M.M., I.L.M., J.A.M., J.E.M., J.C.M., S.M.M., P.M., S.M.-S., A.T.M., E.L.M., C.E.M., A.O., M.I.O., H.O., K.H.P., N.S.P., M.A.P.-V., E.A.P., C.A.R., A.J.R., G.R., J.-A.S., N.T.M.S., D.A.S., T.S., H.P.N.S., S.G.S., W.K.S., S.S., H.S., G.S., R.T.S., E. Souied, E. Souzeau, D.S., Z.S., A.S., A.G.T., B.T., E.E.T., C.M.v.D., C.N.v.S., B.J.V., J.J.W., B.H.F.W., D.E.W., C.W., A.W., Z.Y., J.R.W.Y., D.Z. and K.Z.

Phenotype committee. I.K.K. (lead), S.K.I. (lead), M.D. (lead), G.H.S.B., E.Y.C., I.C., A.I.d.H., S.F., M.B.G., J.L.H., I.M.H., A.W.H., C.C.W.K., B.E.K.K., M.L.K., R.K., T. Léveillard, A.J.L., K.H.P., J.J.W. and K.Z.

Data analysis. Team 1: quality control of data: J.L.B.-G., M.D., L.G.F., M. Gorski, W.I. and I.K.K. Team 2: single-variant analysis: L.G.F. (lead), I.M.H. (lead), G.R.A. (lead), W.I. (lead), J.L.B.-G., G.H.S.B., V.C., M.D., M. Gorski, F.G., M. Grunin, J.L.H., R.P.I., S.K.I., C.C.W.K., M.O., K.S. and X.Z. Team 3: pathway and rare variant burden analysis: L.G.F. (lead), J.N.C.B. (lead), M.S. (lead), G.R.A., M.A.B., M. Brooks, G.H.S.B., M.D.C., M.D., E.K.d.J., A.I.d.H., L.A.F., F.G., J.L.H., I.M.H., J.D.H., W.I., R.P.I., S.K.I., Y.J., M.A.M., M.O., M.A.P.-V., R.J.S., W.K.S., K.S., A.S., B.H.F.W., D.E.W. and X.Z. Team 4: analysis of non-SNP variation: R.P.I. (lead), S.K.I. (lead), P.N.B. (lead), G.R.A., M.D.C., L.G.F. and J.L.H. Team 5: functional data analysis: D.S. (lead), B.H.F.W. (lead), M.D. (lead), S.K.I. (lead), V.C., J.N.C.B., M.D.C., E.K.d.J., A.I.d.H., S.F., L.G.F., F.G., J.L.H., C.H., I.M.H., W.I., D.J.M., M.A.M., R.R., C.M.S., A.S. and X.Z.

Design of overall experiment. G.R.A., M.D., L.G.F., J.L.H., I.M.H., S.K.I., M.A.P.-V. and B.H.F.W.

Genotyping and quality control. K.F.D. (lead), J.R. (lead), L.G.F. (lead), M. Gorski (lead), G.R.A., J.L.B.-G., M.D.C., F.G., J.L.H., I.M.H., J.D.H., W.I., M.O. and X.Z.

Writing team. L.G.F. (lead), I.M.H. (lead), G.R.A., J.N.C.B., M.D., J.L.H., W.I., S.K.I., I.K.K., D.S. and B.H.F.W.

Critical review of manuscript. G.R.A., R.A., P.N.B., M.H.B., I.C., J.N.C.B., M.D., S.F., A.I.d.H., L.A.F., L.G.F., M.B.G., S.A.H., J.L.H., C.H., I.M.H., A.W.H., W.I., S.K.I., I.K.K., C.C.W.K., B.E.K.K., M.L.K., R.K., T. Léveillard, A.J.L., P.M., A.T.M., K.H.P., N.S.P., M.A.P.-V., D.A.S., D.S., A.S., J.J.W., B.H.F.W., D.E.W., J.R.W.Y. and K.Z.

Steering committee of IAMDGC. A.S., G.R.A., A.W.H., M.H.B., K.Z., B.H.F.W., I.M.H., M.D., L.A.F., K.H.P., I.K.K., D.S., T. Léveillard, A.J.L., I.C., S.K.I., S.A.H., N.S.P., B.E.K.K., R.K., D.A.S., M.A.P.-V., P.M., J.J.W., R.A., A.T.M., J.R.W.Y., J.L.H., S.F., A.I.d.H., P.N.B., M.L.K., M.B.G., D.E.W., C.H. and C.C.W.K.

Senior executive committee of IAMDGC. G.R.A., M.D., J.L.H., S.K.I., M.A.P.-V. and B.H.F.W.

Competing interests

D.E.W. and M.B.G. have inventor status on patents held by the University of Pittsburgh regarding the 10q26 AMD susceptibility locus. V.C., A.T.M. and J.R.W.Y. are co-inventors or beneficiaries of patents related to genetic discoveries in AMD. I.C. serves as a consultant for Novartis, Bayer, Allergan and Lycored. L.G.F. and B.H.F.W. receive royalties for AMD-related patents held by the University of Regensburg, G.R.A., A.S., M.I.O. and K.E.B. receive royalties for AMD-related patents held by the University of Michigan and G.R.A. is on the Scientific Advisory Board for the Regeneron Genetics Center. P.M. holds a consultant position for Bayer and Novartis. A.J.L. has acted as a consultant to Bayer, Allergan, Roche and Novartis. S.G.S. has acted as a consultant to Alimera and Bausch + Lomb and has received writing fees from Vindico.

Corresponding authors

Correspondence to Sudha K Iyengar or Gonçalo R Abecasis or Iris M Heid.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4, Supplementary Tables 1–20 and Supplementary Note.

  2. 2.

    Supplementary Data Set 1: LocusZoom plots for each of the 52 identified signals.

    Regional plots showing single-variant association P values of variants around each of the 52 index variants. Shown are also the location/direction of underlying genes and the location of the variants in the 95% credible sets.

Excel files

  1. 1.

    Supplementary Data Set 2: Extended results of the 34 lead variants in non-European subjects.

    We analyzed the association of advanced AMD compared to control subjects in Asian (473 cases, 1,099 controls), African (52 cases, 361 controls) and ‘other ancestry’ (254 cases, 694 controls) groups for our 34 lead variants. Shown are frequencies, odds ratios and P values from the Firth-corrected logistic regression for all analyses.

  2. 2.

    Supplementary Data Set 3: Variants in 95% credible sets and their annotation.

    For each of the 52 index variants, the 95% credible set contains the minimal set of variants that add up to >95% posterior probability.

  3. 3.

    Supplementary Data Set 4: Details about the identified rare protein-altering variants in CFH, CFI, TIMP3 and SLC18A8 that we found to be enriched in AMD cases (Table 2).

    Here we show the variants of each gene below the optimal risk allele frequency that contributed to the observed significant burden.

  4. 4.

    Supplementary Data Set 5: Genes in the 34 identified AMD locus regions.

    Stated are all genes that overlap with the 34 AMD locus regions (defined by the 52 identified variants and their proxies (r2 ≥0.5, ±500 kb) as well as an indicator of whether this gene was also among the 368 genes in the narrow AMD locus regions (defined by 52 identified variants and their proxies (r2 ≥0.5, ±100 kb).

  5. 5.

    Supplementary Data Set 6: Gene expression in retina and RPE/choroid for genes in 34 narrow AMD regions.

    Gene expression in human retina tissue as well as retina pigment epithelium (RPE) or human choroid tissue for the 368 genes in 34 narrow AMD locus regions have been provided by two laboratories, the Weber laboratory and the Stambolian laboratory (Online Methods). A consensus rating was obtained by defining the gene as ‘expressed’ if it was expressed in both data sets. It was defined as ‘not expressed’ if it was found as not expressed in at least one laboratory and as ‘missing’ otherwise.

  6. 6.

    Supplementary Data Set 7: Relevant eye phenotypes in genetic mouse models in 33 genes in the 34 narrow AMD regions.

    We queried databases and conducted a literature search (Online Methods) for the 368 genes in the 34 narrow AMD regions and found relevant eye phenotypes for 33 of these genes.

  7. 7.

    Supplementary Data Set 8

    Approved and experimental drug targets among 368 genes in narrow AMD regions. We queried the DrugBank database (version 4.1; see URLs) to obtain overlap of the 368 genes in our 34 identified AMD regions with the drug target list. We found 31 of these genes to be a current drug target.

  8. 8.

    Supplementary Data Set 9: Summary of biological and statistical evidence for genes in narrow AMD regions.

    For all genes in the narrow AMD loci (Supplementary Data Set 5), we gathered evidence on whether the gene (i) was expressed in retina or RPE/choroid (Supplementary Data Set 6), (ii) had a retina or RPE/choroid phenotype in genetic mouse models (Supplementary Data Set 7), (iii) contained ≥1 variant in a 95% credible set by extending to ±50 kb around the gene (Supplementary Data Set 3) or (iv) had a significant rare variant burden (Table 2 and Supplementary File 4). Furthermore, we derived whether the credible set variants in the gene (±50 kb) contained (v) a protein-altering variant, (vi) a variant in the 5′ or 3′ UTR, (vii) another exonic coding variant or (viii) a putative promoter variant (Supplementary Data Set 3) or whether the gene (ix) was in an enriched molecular pathway (Supplementary Table 13) or (x) linked to an approved or experimental drug (Supplementary Data Set 8).

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DOI

https://doi.org/10.1038/ng.3448

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