Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus

Journal name:
Nature Genetics
Volume:
42,
Pages:
426–429
Year published:
DOI:
doi:10.1038/ng.565
Received
Accepted
Published online
Corrected online
Corrected online

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22–23, rs2056626, P = 2.09 × 10−7 in the discovery samples, P = 3.39 × 10−9 in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 × 10−18), IRF5 (P = 1.86 × 10−13) and STAT4 (P = 3.37 × 10−9) gene regions as SSc genetic risk factors.

At a glance

Figures

  1. Manhattan plot of the GWAS of the discovery cohort comprising 2,346 SSc cases and 5,193 healthy controls.
    Figure 1: Manhattan plot of the GWAS of the discovery cohort comprising 2,346 SSc cases and 5,193 healthy controls.

    The −log10 of the Mantel-Haenszel test P value of 279,621 SNPs after correction by λ is plotted against its physical chromosomal position. Chromosomes are shown in alternate colors. SNPs above the red line represent those with a P value <5 × 10−7. Plot corresponds to the combined analysis of the study cohorts.

  2. Forest plot showing the odds ratios and confidence intervals of the CD247 association in the various populations studied in the discovery and replication cohorts.
    Figure 2: Forest plot showing the odds ratios and confidence intervals of the CD247 association in the various populations studied in the discovery and replication cohorts.

Change history

Corrected online 16 April 2010
In the version of this article initially published online, the name of author Annemie J. Schuerwegh was misspelled. The error has been corrected for the print, PDF, and HTML versions of this article.
Corrected online 23 March 2011
In the version of this article initially published, incorrect affiliations were published for Lorenzo Beretta and Raffaella Scorza. The correct affiliation for Lorenzo Beretta and Raffaella Scorza is "Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan". The error has been corrected in the HTML and PDF versions of the article.

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Author information

  1. These authors contributed equally to this work.

    • Timothy R D J Radstake,
    • Olga Gorlova,
    • Blanca Rueda,
    • Jose-Ezequiel Martin,
    • Bobby P C Koeleman,
    • Frank C Arnett,
    • Javier Martin &
    • Maureen D Mayes

Affiliations

  1. Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

    • Timothy R D J Radstake,
    • Madelon C Vonk,
    • Jasper C Broen &
    • Piet L C M van Riel
  2. Department of Epidemiology, M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Olga Gorlova,
    • Jun Ying,
    • Younghun Han,
    • Shih-Feng Weng &
    • Christopher I Amos
  3. Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.

    • Blanca Rueda,
    • Jose-Ezequiel Martin,
    • Rogelio Palomino-Morales &
    • Javier Martin
  4. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Behrooz Z Alizadeh,
    • Ruben van 't Slot,
    • Annet Italiaander,
    • Roel A Ophoff &
    • Bobby P C Koeleman
  5. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

    • Marieke J Coenen
  6. Department of Rheumatology, Vrije Universiteit (VU) Medical Centre, Nijmegen, The Netherlands.

    • Alexandre E Voskuyl
  7. Department of Rheumatology, University of Leiden, Nijmegen, The Netherlands.

    • Annemie J Schuerwegh
  8. University of California Los Angeles Center for Neurobehavioral Genetics, Los Angeles, California.

    • Roel A Ophoff
  9. Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany.

    • Gabriela Riemekasten
  10. Department of Dermatology, University of Cologne, Cologne, Germany.

    • Nico Hunzelmann
  11. Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain.

    • Carmen P Simeon
  12. Servicio de Medicina Interna, Hospital Clínico Universitario, Granada, Spain.

    • Norberto Ortego-Centeno
  13. Servicio de Reumatología, Hospital Marqués de Valdecilla, Santander, Spain.

    • Miguel A González-Gay &
    • Patricia Carreira
  14. Servicio de Inmunología, Hospital Virgen del Rocío, Sevilla, Spain.

    • María F González-Escribano
  15. University of Brescia, Brescia, Italy.

    • Paolo Airo
  16. University of Newcastle, Newcastle Upon Tyne, UK.

    • Jaap van Laar
  17. Department of Rheumatology and Epidemiology, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

    • Ariane Herrick &
    • Jane Worthington
  18. University of Lund, Lund, Sweden.

    • Roger Hesselstrand
  19. University of Ghent, Ghent, Belgium.

    • Vanessa Smith &
    • Filip de Keyser
  20. University of Leuven, Leuven, Belgium.

    • Fredric Houssiau
  21. University of Glasgow, Glasgow, UK.

    • Meng May Chee,
    • Rajan Madhok &
    • Paul Shiels
  22. University of Antwerpen, Antwerpen, Belgium.

    • Rene Westhovens
  23. Ruhr University of Bochum, Bochum, Germany.

    • Alexander Kreuter
  24. University of Vienna, Vienna, Austria.

    • Hans Kiener
  25. Department of Genetics, University of Ghent, Ghent, Belgium.

    • Elfride de Baere
  26. University of Hannover, Hannover, Germany.

    • Torsten Witte
  27. Karolinska Institute, Stockholm, Sweden.

    • Leonid Padykov &
    • Lars Klareskog
  28. Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy.

    • Lorenzo Beretta &
    • Rafaella Scorza
  29. Institute of Immunology, Oslo University Hospital, Oslo, Norway.

    • Benedicte A Lie
  30. Department of Rheumatology, Rikshospitalet, Oslo University Hospital, Oslo, Norway.

    • Anna-Maria Hoffmann-Vold
  31. Hospital 12 de Octubre, Madrid, Spain.

    • Patricia Carreira
  32. Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

    • John Varga &
    • Monique Hinchcliff
  33. Feinstein Institute of Medical Research, Manhasset, New York, USA.

    • Peter K Gregersen &
    • Annette T Lee
  34. Johns Hopkins University Medical Center, Baltimore, Maryland, USA.

    • Fredrick M Wigley &
    • Laura Hummers
  35. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • J Lee Nelson
  36. The University of Texas Health Science Center–Houston, Houston, Texas, USA.

    • Sandeep K Agarwal,
    • Shervin Assassi,
    • Pravitt Gourh,
    • Filemon K Tan,
    • Frank C Arnett &
    • Maureen D Mayes
  37. A full list of members is provided in the Supplementary Note.

    • $affiliationAuthor

Contributions

Study Design: T.R.D.J.R., O.G., B.R., J.-E.M., B.P.C.K., F.C.A., J.M., M.D.M.

Collection of data: T.R.D.J.R., M.J.C., M.C.V., A.E.V., A.J.S., J.C.B., B.A.L., A.-M.H.-V., R.A.O., G.R., N.H., C.P.S., N.O.-C., M.A.G.-G., M.F.G.-E., P.A., J.v.L., A.H., J.W., R.H., V.S., F.d.K., F.H., M.M.C., R.M., P.S., R.W., A.K., H.K., E.d.B., T.W., L.P., L.K., L.B., R.S., J.V., M.H., P.G., J.L.N., F.M.W., L.H., P.C., S.A.

Interpretation and analysis of results: T.R.D.J.R., O.G., B.R., J.-E.M., B.Z.A., R.P.-M., J.Y., Y.H., S.-F.W., R.v.'t.S., P.G., A.T.L., C.I.A., S.K.A., B.P.C.K., J.M., M.D.M., A.I., P.C., S.A., P.K.G.

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

Project conception: T.R.D.J.R., B.P.C.K., F.C.A., J.M., M.D.M.

Competing financial interests

The authors declare no competing financial interests.

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Supplementary information

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    Supplementary Tables 1–5, Supplementary Figures 1–4 and Supplementary Note

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