Letter | Published:

Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

Nature Genetics volume 46, pages 11261130 (2014) | Download Citation

Abstract

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10−8 for rs6445055), two on chromosome 9 (P = 2.80 × 10−11 for rs2472493 near ABCA1 and P = 6.39 × 10−11 for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10−11 for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

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Acknowledgements

We gratefully acknowledge the contributions of all participants who volunteered within each cohort and the personnel responsible for the recruitment and administration of each study. We also thank the various funding sources that made this work possible. Complete funding information and acknowledgments can be found in the Supplementary Note.

Author information

Author notes

    • Pirro G Hysi
    • , Ching-Yu Cheng
    • , Henriët Springelkamp
    • , Stuart Macgregor
    • , Jessica N Cooke Bailey
    •  & Robert Wojciechowski

    These authors contributed equally to this work.

    • Ananth Viswanathan
    • , David A Mackey
    • , Jamie E Craig
    • , Janey L Wiggs
    • , Cornelia M van Duijn
    • , Christopher J Hammond
    •  & Tin Aung

    These authors jointly directed this work.

Affiliations

  1. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Pirro G Hysi
    • , Abhishek Nag
    • , Cristina Venturini
    • , Timothy D Spector
    • , Kerrin S Small
    •  & Christopher J Hammond
  2. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.

    • Ching-Yu Cheng
    • , Eranga Vithana
    • , Jiemin Liao
    • , Yingfeng Zheng
    • , Seang-Mei Saw
    • , Tien-Yin Wong
    •  & Tin Aung
  3. Department of Ophthalmology, National University of Singapore and National University Health System, Singapore.

    • Ching-Yu Cheng
    • , Eranga Vithana
    • , Chiea-Chuen Khor
    • , Jiemin Liao
    • , Seang-Mei Saw
    • , Tien-Yin Wong
    •  & Tin Aung
  4. Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore.

    • Ching-Yu Cheng
    • , Yik-Ying Teo
    • , Yingfeng Zheng
    • , E-Shyong Tai
    • , Seang-Mei Saw
    •  & Tien-Yin Wong
  5. Duke–National University of Singapore Graduate Medical School, Singapore.

    • Ching-Yu Cheng
    • , Eranga Vithana
    • , E-Shyong Tai
    •  & Seang-Mei Saw
  6. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Henriët Springelkamp
    • , Wishal D Ramdas
    • , Julia E Richards
    • , Dominiek D G Despriet
    • , Johannes R Vingerling
    • , Roger C W Wolfs
    •  & Caroline C W Klaver
  7. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Henriët Springelkamp
    • , Wishal D Ramdas
    • , Najaf Amin
    • , Lennart C Karssen
    • , Adriana I Iglesias
    • , Elisabeth M van Leeuwen
    • , Leonieke M E van Koolwijk
    • , Fernando Rivadeneira
    • , André G Uitterlinden
    • , Albert Hofman
    • , Johannes R Vingerling
    • , Caroline C W Klaver
    •  & Cornelia M van Duijn
  8. Statistical Genetics, QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, Brisbane, Queensland, Australia.

    • Stuart Macgregor
    •  & Gabriel Cuellar-Partida
  9. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA.

    • Jessica N Cooke Bailey
    •  & Jonathan L Haines
  10. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

    • Robert Wojciechowski
  11. National Human Genome Research Institute, US National Institutes of Health, Baltimore, Maryland, USA.

    • Robert Wojciechowski
    • , Claire L Simpson
    •  & Joan E Bailey-Wilson
  12. Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Veronique Vitart
  13. Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

    • Alex W Hewitt
    • , Sandra E Staffieri
    • , Lisa Kearns
    •  & David A Mackey
  14. Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany.

    • René Höhn
    • , Alireza Mirshahi
    •  & Norbert Pfeiffer
  15. Institute of Ophthalmology, University College London, London, UK.

    • Cristina Venturini
  16. deCODE/Amgen, Reykjavik, Iceland.

    • Gudmar Thorleifsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  17. Division of Human Genetics, Genome Institute of Singapore, Singapore.

    • Chiea-Chuen Khor
  18. Eye Clinic, Reykjavik, Iceland.

    • Arni B Stefansson
  19. Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China.

    • Ya Xing Wang
    •  & Liang Xu
  20. Department of Internal Medicine II, University Medical Center Mainz, Mainz, Germany.

    • Philipp S Wild
  21. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Ayse B Ozel
    •  & Jun Z Li
  22. National Health Service (NHS) Princess Alexandra Eye Pavilion, Edinburgh, UK.

    • Brian W Fleck
  23. Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.

    • Tanja Zeller
  24. Department of Statistics and Applied Probability, National University of Singapore, Singapore.

    • Yik-Ying Teo
  25. Duke Eye Center, Duke University, Durham, North Carolina, USA.

    • Xiaoyan Luo
    •  & Terri L Young
  26. Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA.

    • R Rand Allingham
    •  & Michael A Hauser
  27. Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Lübeck, Germany.

    • Andrea Senft
  28. INSERM, UMR 774, Lille, France.

    • Céline Bellenguez
    •  & Philippe Amouyel
  29. Université Lille 2, Lille, France.

    • Céline Bellenguez
    •  & Philippe Amouyel
  30. Institut Pasteur de Lille, Lille, France.

    • Céline Bellenguez
    •  & Philippe Amouyel
  31. Centre for Population Health Sciences, University of Edinburgh Medical School, Edinburgh, UK.

    • James F Wilson
  32. Channing Division of Network Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Jae H Kang
    •  & Louis R Pasquale
  33. Department of Ophthalmology, Landspitali National University Hospital, Reykjavik, Iceland.

    • Vesteinn Jonsson
  34. Human Genetics and Genomic Medicine, Faulty of Medicine, University of Southampton, Southampton, UK.

    • Sarah Ennis
  35. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.

    • Sayoko E Moroi
  36. Genetic Epidemiology, QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, Brisbane, Queensland, Australia.

    • Nicholas G Martin
  37. Department of Ophthalmology, University Medical Center Groningen, Groningen, the Netherlands.

    • Nomdo M Jansonius
  38. Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia.

    • Seyhan Yazar
    •  & David A Mackey
  39. Department of Medicine, National University of Singapore and National University Health System, Singapore.

    • E-Shyong Tai
  40. Centre Hospitalier Régional Universitaire de Lille, Lille, France.

    • Philippe Amouyel
  41. Department of Ophthalmology, Portsmouth Hospitals NHS Trust, Portsmouth, UK.

    • James Kirwan
  42. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • Michael A Hauser
  43. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Fridbert Jonasson
  44. The University of Queensland Diamantina Institute, Woollongabba, Queensland, Australia.

    • Paul Leo
  45. Department of Ophthalmology, Harvard Medical School and Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.

    • Stephanie J Loomis
    • , Louis R Pasquale
    •  & Janey L Wiggs
  46. Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.

    • Rhys Fogarty
    • , Kathryn P Burdon
    •  & Jamie E Craig
  47. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Fernando Rivadeneira
    •  & André G Uitterlinden
  48. Netherlands Consortium for Healthy Ageing, Netherlands Genomics Initiative, The Hague, the Netherlands.

    • Fernando Rivadeneira
    • , André G Uitterlinden
    •  & Albert Hofman
  49. Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.

    • Karl J Lackner
  50. Netherlands Institute for Neuroscience, Amsterdam, the Netherlands.

    • Paulus T V M de Jong
  51. Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.

    • Paulus T V M de Jong
  52. Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands.

    • Paulus T V M de Jong
  53. School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.

    • Craig E Pennell
  54. Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Ben A Oostra
  55. Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

    • Andrew J Lotery
  56. Université Bordeaux, ISPED (Institut de Santé Publique, d'Epidémiologie et de Développement), Bordeaux, France.

    • Cécilia Maubaret
    •  & Cécile Delcourt
  57. INSERM, Centre INSERM U897 Epidemiologie-Biostatistique Bordeaux, Bordeaux, France.

    • Cécilia Maubaret
    •  & Cécile Delcourt
  58. Glaucoma Service, Rotterdam Eye Hospital, Rotterdam, the Netherlands.

    • Hans G Lemij
  59. National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, UK.

    • Ananth Viswanathan

Consortia

  1. BMES GWAS Group

    A full list of members appears in the Supplementary Note.

  2. NEIGHBORHOOD Consortium

    A full list of members appears in the Supplementary Note.

  3. Wellcome Trust Case Control Consortium 2

    A full list of members appears in the Supplementary Note.

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Contributions

P.G.H., C.-Y.C., H.S., S.M., J.N.C.B. and R.W. performed analyses and drafted the manuscript. S.M., A.J.L., J.E.B.-W., V.V., L.R.P., N.P., C.D., A.V., D.A.M., J.E.C., J.L.W., C.M.v.D., C.J.H. and T.A. jointly conceived the project and supervised the work. P.G.H., H.S., R.W., A.N., A.W.H., A.M., C.V., R.H., G.T., B.A.O., S.-M.S., W.D.R., E.V., C.-C.K., D.D.G.D., J.L., J.L.H., Y.X.W., F.R., P.S.W., H.G.L., A.B.O., J.Z.L., B.W.F., R.C.W.W., T.Z., S.E.S., Y.-Y.T., G.C.-P., X.L., R.R.A., J.E.R., A.S., Y.Z., C.B., A.I.I., L.X., J.F.W., J.H.K., L.C.K., K.S., V.J., A.G.U., N.M.J., U.T., J.R.V., N.A., S.E., S.E.M., N.G.M., S.Y., E.-S.T., E.M.v.L., P.A., J.K., M.A.H., F.J., P.L., A.H., S.J.L., R.F., L.K., P.T.V.M.d.J., K.J.L., C.L.S., C.E.P., L.M.E.v.K., C.M., C.C.W.K., K.P.B., T.D.S., T.-Y.W., D.A.M., J.E.C. and A.B.S. were responsible for cohort-specific activities, data generation and analyses. T.L.Y. and K.S.S. were responsible for expression and eQTL work. P.G.H., C.-Y.C., H.S., S.M., T.-Y.W., D.A.M., J.L.W., C.M.v.D. and C.J.H. critically reviewed the manuscript.

Competing interests

The authors declare competing financial interests. G.T., K.S. and U.T. are employees of deCODE Genetics/Amgen. C.D. has a consultant role for Laboratoires Théa, Novartis, Bausch+Lomb.

Corresponding authors

Correspondence to Christopher J Hammond or Tin Aung.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1–10, Supplementary Figure 1–3 and Supplementary Note.

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DOI

https://doi.org/10.1038/ng.3087

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