Abstract

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (fcase) = 0.51%; control frequency (fcontrol) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (fcase = 1.06%; fcontrol = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

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Acknowledgements

We thank all study participants for their generous volunteering. We thank B. Li, W. Chen, C. Sidore, T. Teslovich, L. Fritsche and M. Boehnke for useful discussion and suggestions. This project was supported by grants from the US National Institutes of Health (National Eye Institute, National Human Genome Research Institute; grants EY022005, HG007022, HG005552, EY016862, U54HG003079 and EY09859); the Medical Research Council, UK (grant G0000067); the Deutsche Forschungsgemeinschaft (grant WE1259/19-2); the Alcon Research Institute; The UK Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and the UCL Institute of Ophthalmology; Research to Prevent Blindness (New York); the Thome Memorial Foundation; the Harold and Pauline Price Foundation; and the National Health and Medical Research Council of Australia (NHMRC) Clinical Research Excellence (grant 529923, NHMRC practitioner fellowship 529905 and NHMRC Senior Research Fellowship 1028444). The study was also supported by the Intramural Research Program (Computational Medicine Initiative) of the National Eye Institute. The Centre for Eye Research Australia (CERA) receives operational infrastructure support from the Victorian Government. The views expressed in the publication are those of the authors and not necessarily those of their employers or the funders.

Author information

Author notes

    • Xiaowei Zhan
    • , David E Larson
    •  & Chaolong Wang

    These authors contributed equally to this work.

    • Elaine R Mardis
    • , Anand Swaroop
    •  & Goncalo R Abecasis

    These authors jointly directed this work.

Affiliations

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

    • Xiaowei Zhan
    • , Chaolong Wang
    • , Jennifer Bragg-Gresham
    • , Goo Jun
    • , Youna Hu
    • , Hyun Min Kang
    • , Dajiang Liu
    •  & Goncalo R Abecasis
  2. The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.

    • David E Larson
    • , Daniel C Koboldt
    • , Robert S Fulton
    • , Lucinda L Fulton
    • , Catrina C Fronick
    • , Richard K Wilson
    •  & Elaine R Mardis
  3. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Chaolong Wang
  4. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, USA.

    • Yuri V Sergeev
  5. Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, Michigan, USA.

    • Kari E Branham
    • , Mohammad Othman
    •  & John R Heckenlively
  6. Neurobiology–Neurodegeneration and Repair Laboratory, National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Matthew Brooks
    • , Rinki Ratnapriya
    • , Alexis Boleda
    •  & Anand Swaroop
  7. Institute of Human Genetics, University of Regensburg, Regensburg, Germany.

    • Felix Grassmann
    •  & Bernhard H F Weber
  8. Southwest Eye Center, Stuttgart, Germany.

    • Claudia von Strachwitz
  9. Center for Human Genetics Research, Vanderbilt University Medical School, Nashville, Tennessee, USA.

    • Lana M Olson
    •  & Jonathan L Haines
  10. Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, Tennessee, USA.

    • Lana M Olson
    •  & Jonathan L Haines
  11. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.

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

    • Gabriëlle H S Buitendijk
    • , Albert Hofman
    • , Cornelia M van Duijn
    •  & Caroline C W Klaver
  13. Netherlands Consortium for Healthy Aging, Netherlands Genomics Initiative, The Hague, The Netherlands.

    • Albert Hofman
  14. UCL Institute of Ophthalmology, University College London, London, UK.

    • Valentina Cipriani
    • , Anthony T Moore
    •  & John R W Yates
  15. Moorfields Eye Hospital, London, UK.

    • Valentina Cipriani
    • , Anthony T Moore
    •  & John R W Yates
  16. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

    • Humma Shahid
    •  & John R W Yates
  17. Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.

    • Humma Shahid
  18. Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Yingda Jiang
    •  & Daniel E Weeks
  19. Department of Health Promotion and Development, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Yvette P Conley
  20. Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.

    • Denise J Morgan
    •  & Margaret M DeAngelis
  21. Retina Service and Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.

    • Ivana K Kim
  22. Texas Biomedical Research Institute, San Antonio, Texas, USA.

    • Matthew P Johnson
    •  & John Blangero
  23. Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.

    • Stuart Cantsilieris
    • , Andrea J Richardson
    • , Robyn H Guymer
    •  & Paul N Baird
  24. Department of Ophthalmology, Shiley Eye Center, University of California, San Diego, La Jolla, California, USA.

    • Hongrong Luo
    • , Hong Ouyang
    • , Mindy M Zhang
    •  & Kang Zhang
  25. Institute for Genomic Medicine, University of California, San Diego, La Jolla, California, USA.

    • Hongrong Luo
    • , Hong Ouyang
    • , Mindy M Zhang
    •  & Kang Zhang
  26. Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Christoph Licht
  27. Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Fred G Pluthero
  28. Macular Degeneration Center, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA.

    • Michael L Klein
  29. Section on Biomedical Genetics, Department of Medicine, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA.

    • Lindsay A Farrer
  30. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Lindsay A Farrer
  31. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Lindsay A Farrer
  32. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Lindsay A Farrer
  33. Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Lindsay A Farrer
  34. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Daniel E Weeks
  35. Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

    • Michael B Gorin
  36. John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.

    • Margaret A Pericak-Vance
  37. Division of Epidemiology and Clinical Applications, National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Emily Y Chew
  38. Department of Ophthalmology and Human Genetics, University of Pennsylvania Medical School, Philadelphia, Pennsylvania, USA.

    • Dwight Stambolian

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Contributions

R.K.W., J.R.H., E.Y.C., D.S., E.R.M., A.S. and G.R.A. conceived, designed and supervised the experiments. X.Z. and G.R.A. wrote the initial version of the manuscript. X.Z., D.E.L., C.W. and D.C.K. analyzed the data. D.E.L., D.C.K., R.S.F., L.L.F. and C.C.F. supervised data generation. C.W. developed statistical methodology. Y.V.S. analyzed protein structures. K.E.B. supervised sample and data collection. J.B.-G., G.J., Y.H., H.M.K. and D.L. contributed data and analysis tools. M.B., R.R. and A.B. assisted in laboratory experiments. M.O. and F.G. carried out experimental studies (genotyping and data analysis) for the Michigan and Regensburg samples, respectively. C.v.S. recruited the family members of sporadic AMD cases and controls and collected peripheral blood samples for the Regensburg study. L.M.O., M.A.P.-V. and J.L.H. provided results and analysis for the Vanderbilt/Miami samples. G.H.S.B., A.H., C.M.v.D. and C.C.W.K. provided results and analysis for samples from the Rotterdam Study, Erasmus Medical Center. V.C., A.T.M., H.S. and J.R.W.Y. provided results and analysis for the Cambridge AMD Study samples. Y.J., Y.P.C., D.E.W. and M.B.G. provided results and analysis for the University of California, Los Angeles/University of Pittsburgh samples. D.J.M., I.K.K., L.A.F. and M.M.D. provided results and analysis for the Utah samples. M.P.J., J.B. and M.L.K. provided results and analysis for the Oregon Health Sciences Center samples. S.C., A.J.R., R.H.G. and P.N.B. provided results and analysis for the University of Melbourne samples. H.L., H.O., M.M.Z. and K.Z. provided results and analysis for the University of California, San Diego samples. C.L. and F.G.P. provided results and analysis for a cohort of individuals with aHUS. B.H.F.W. was involved in the design and planning of the Southern Germany AMD Study. B.H.F.W. participated in study coordination and critically read the manuscript. All authors have critically commented on this manuscript.

Competing interests

G.R.A., X.Z., C.W. and A.S. are potential beneficiaries of a University of Michigan patent that is now pending that describes association between variant p.Lys155Gln encoded by the complement 3 gene and AMD.

Corresponding author

Correspondence to Goncalo R Abecasis.

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https://doi.org/10.1038/ng.2758

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