Article | Published:

Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus

Nature Genetics volume 45, pages 155163 (2013) | Download Citation

Abstract

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10−8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4–1.88, P = 2.7 × 10−10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29–1.68, P = 4.9 × 10−9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10−4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT.

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Acknowledgements

A list of acknowledgments by study is provided in the Supplementary Note.

Author information

Author notes

    • Yi Lu
    • , Veronique Vitart
    • , Kathryn P Burdon
    • , Chiea Chuen Khor
    •  & Andrew J Lotery

    These authors contributed equally to this work.

    • Janey L Wiggs
    • , Chi P Pang
    • , Unnur Thorsteinsdottir
    • , Christopher J Hammond
    • , Cornelia M van Duijn
    • , Michael A Hauser
    • , Yaron S Rabinowitz
    • , Norbert Pfeiffer
    • , David A Mackey
    • , Jamie E Craig
    • , Stuart Macgregor
    •  & Tien Y Wong

    These authors jointly directed this work.

Affiliations

  1. Queensland Institute of Medical Research, Statistical Genetics, Herston, Brisbane, Queensland, Australia.

    • Yi Lu
    •  & Stuart Macgregor
  2. Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Veronique Vitart
    • , Caroline Hayward
    •  & Alan F Wright
  3. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.

    • Kathryn P Burdon
    • , David P Dimasi
    • , Richard A Mills
    •  & Jamie E Craig
  4. Singapore Eye Research Institute, Singapore.

    • Chiea Chuen Khor
    • , Eranga N Vithana
    • , Belinda K Cornes
    • , Wan-Ting Tay
    • , Ching-Yu Cheng
    •  & Tin Aung
  5. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Chiea Chuen Khor
    • , Eranga N Vithana
    • , Ching-Yu Cheng
    •  & Tin Aung
  6. Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

    • Chiea Chuen Khor
    • , E Shyong Tai
    • , Ching-Yu Cheng
    • , Jianjun Liu
    • , Seang Mei Saw
    •  & Tien Y Wong
  7. Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore.

    • Chiea Chuen Khor
    • , Jianjun Liu
    •  & Jia-Nee Foo
  8. Regenerative Medicine Institute, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Division of Surgical Research, Los Angeles, California, USA.

    • Yelena Bykhovskaya
    •  & Yaron S Rabinowitz
  9. Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.

    • Alireza Mirshahi
    • , René Hoehn
    • , Franz Grus
    •  & Norbert Pfeiffer
  10. Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

    • Alex W Hewitt
    •  & David A Mackey
  11. Lions Eye Institute, Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia.

    • Alex W Hewitt
    • , Seyhan Yazar
    •  & David A Mackey
  12. Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

    • Demelza Koehn
    •  & Michael G Anderson
  13. Department of Twin Research and Genetic Epidemiology, King's College London School of Medicine, St Thomas' Hospital, London, UK.

    • Pirro G Hysi
    • , Timothy D Spector
    •  & Christopher J Hammond
  14. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Wishal D Ramdas
    • , Virginie J M Verhoeven
    • , Roger Wolfs
    • , Henriët Springelkamp
    •  & Caroline C W Klaver
  15. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

    • Wishal D Ramdas
    • , Virginie J M Verhoeven
    • , Roger Wolfs
    • , Henriët Springelkamp
    • , Caroline C W Klaver
    •  & Cornelia M van Duijn
  16. University Heart Center Hamburg, Clinic for General and Interventional Cardiology, Hamburg, Germany.

    • Tanja Zeller
  17. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • E Shyong Tai
  18. Centre for Quantitative Medicine, Office of Clinical Sciences, Duke-National University of SIngapore Graduate Medical School, Singapore.

    • Ching-Yu Cheng
  19. deCODE genetics, Reykjavik, Iceland.

    • Gudmar Thorleifsson
    • , Kari Stefansson
    •  & Unnur Thorsteinsdottir
  20. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Kari Stefansson
    • , Fridbert Jonasson
    •  & Unnur Thorsteinsdottir
  21. Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Western Australia, Australia.

    • Jenny Mountain
  22. School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.

    • Wei Ang
    •  & Craig Pennell
  23. Institut de Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche de Santé (UMRS) 937, Pierre and Marie Curie University and Medical School, Paris, France.

    • Raphaële Castagne
  24. Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Mainz, Germany.

    • Karl J Lackner
  25. University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.

    • Jian Yang
  26. Department of Ophthalmology, Landspitali National University Hospital, Reykjavik, Iceland.

    • Fridbert Jonasson
  27. Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, Hong Kong.

    • Dexter Y L Leung
    • , Li J Chen
    • , Clement C Y Tham
    •  & Chi P Pang
  28. Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.

    • Igor Rudan
    • , Harry Campbell
    •  & James F Wilson
  29. Croatian Centre for Global Health, University of Split Medical School, Split, Croatia.

    • Igor Rudan
    •  & Ozren Polasek
  30. Department of Ophthalmology, Hospital Sestre Milosrdnice, Zagreb, Croatia.

    • Zoran Vatavuk
  31. Genetic Epidemiology and Genomic Informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.

    • Jane Gibson
    •  & Sarah Ennis
  32. Clinical Neurosciences Research Grouping, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.

    • Angela J Cree
    •  & Andrew J Lotery
  33. Southampton Eye Unit, Southampton General Hospital, Southampton, UK.

    • Alex MacLeod
    •  & Andrew J Lotery
  34. Department of Public Health, University of Split, Split, Croatia.

    • Ozren Polasek
  35. National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and University College London (UCL) Institute of Ophthalmology, London, UK.

    • Ananth C Viswanathan
  36. Princess Alexandra Eye Pavilion, Edinburgh, UK.

    • Brian Fleck
  37. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Xiaohui Li
    • , Kent D Taylor
    •  & Jerome I Rotter
  38. Cardiovascular Health Research Unit, Departments of Medicine, University of Washington, Seattle, Washington, USA.

    • David Siscovick
  39. Department of Medicine, Duke University, Durham, North Carolina, USA.

    • Megan Ulmer
    • , Allison Ashley-Koch
    •  & Michael A Hauser
  40. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Jun Li
    •  & Ayse B Ozel
  41. Vanderbilt University School of Medicine, Center for Human Genetics Research, Nashville, Tennessee, USA.

    • Brian L Yaspan
    •  & Jonathan L Haines
  42. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.

    • Julia E Richards
    •  & Sayoko E Moroi
  43. Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, Massachusetts, USA.

    • Jae H Kang
    •  & Louis R Pasquale
  44. Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.

    • Louis R Pasquale
    •  & Janey L Wiggs
  45. Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA.

    • R Rand Allingham
    •  & Tien Y Wong
  46. Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Westmead, New South Wales, Australia.

    • Paul Mitchell
    •  & Jie Jin Wang
  47. Center for Human Genetics, Duke University Medical Center, Durham, North Carolina, USA.

    • Terri L Young
  48. Duke-National University of Singapore, Singapore.

    • Terri L Young
  49. Queensland Institute of Medical Research, Genetic Epidemiology, Herston, Brisbane, Queensland, Australia.

    • Nicholas G Martin
  50. Queensland Institute of Medical Research, Molecular Epidemiology, Herston, Brisbane, Queensland, Australia.

    • Grant W Montgomery
  51. Department of Ophthamology and Visual Sciences, University of Iowa, Iowa City, Iowa, USA.

    • Michael G Anderson
  52. Singapore National Eye Centre, Singapore.

    • Tin Aung
  53. Centre for Vision and Vascular Science, Queen's University Belfast, Belfast, UK.

    • Colin E Willoughby
  54. Cornea Genetic Eye Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Yaron S Rabinowitz

Consortia

  1. NEIGHBOR Consortium

    A list of members is provided in the Supplementary Note.

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Contributions

S.M., V.V., D.A.M., T.Y.W. and Y.L. conceived and designed the study, and liaised with the International Glaucoma Genetics Consortium for this project. Y.L. performed the primary analyses. S.M., J.Y., M.U., X.L., C.C.K., E.N.V., T.A., K.P.B., G.T., F.J., V.V., O.P., D.Y.L.L., L.J.C., C.C.Y.T., R.C., D.K., W.A., W.D.R., V.J.M.V., H.S., J.G., A.J.C., A. MacLeod, S.E., P.G.H., Y.B. and X.L. contributed to analysis. S.M. and Y.L. performed pathway analysis. J.E.C., P.M., U.T., A.F.W., N.P., C.P.P., M.G.A., J.L.W., M.A.H., L.R.P., C.E.W., N.G.M., D.A.M., C.M.v.D., T.Y.W., A.J.L., C.J.H. and Y.S.R. were the overseeing principal investigators of the individual studies. J.E.C., K.P.B., D.P.D., R.A.M., G.T., K.S., F.J., U.T., A.F.W., V.V., I.R., Z.V., C.H., O.P., H.C., J.F.W., B.F., N.P., A. Mirshahi, T.Z., R.H., F.G., R.C., K.J.L., C.P.P., D.Y.L.L., L.J.C., C.C.Y.T., M.G.A., D.K., J.L.W., L.R.P., M.U., J. Liu, B.L.Y., A.B.O., J.E.R., S.E.M., J.L.H., J.H.K., L.R.P., R.R.A., A.A.-K., J.L.W., M.A.H., N.G.M., Y.L., G.W.M., S.M., D.A.M., A.W.H., J.M., W.A., S.Y., C.P., T.L.Y., W.D.R., V.J.M.V., R.W., H.S., C.C.W.K., C.M.v.D., C.C.K., E.N.V., B.K.C., W.-T.T., E.S.T., C.-Y.C., J.-N.F., J. Li, S.M.S., T.A., T.Y.W., J.G., A.J.C., A. MacLeod, S.E., A.J.L., P.G.H., T.D.S., T.L.Y. and C.J.H. contributed reagents or methods to the genotyping, phenotyping and data analysis of corneal thickness data sets. J.E.C., K.P.B., D.P.D., R.A.M., C.P.P., D.Y.L.L., L.J.C., C.C.Y.T., J.L.W., L.R.P., M.U., J. Li, B.L.Y., A.B.O., J.E.R., S.E.M., J.L.H., J.H.K., L.R.P., R.R.A., A.A.-K., J.L.W., M.A.H., C.E.W., A.J.L., J.G., A.J.C., A. MacLeod, S.E., Y.S.R., Y.B., X.L., D.S., K.D.T., J.J.W., A.C.V. and J.I.R. contributed reagents or the genotyping, phenotyping and data analysis of the glaucoma, and keratoconus samples. Y.L. and S.M. wrote the first draft of this manuscript. K.P.B., V.V., C.C.K., Y.B., A. Mirshahi, A.W.H., D.K., P.G.H., W.D.R., J.L.W., C.M.v.D., Y.S.R., D.A.M., J.E.C. and T.Y.W. provided critical comments for manuscript revision. All authors reviewed the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Stuart Macgregor or Tien Y Wong.

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Published

DOI

https://doi.org/10.1038/ng.2506

Further reading

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