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Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis

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Abstract

A genome-wide association scan of ∼6.6 million genotyped or imputed variants in 882 Sardinian individuals with multiple sclerosis (cases) and 872 controls suggested association of CBLB gene variants with disease, which was confirmed in 1,775 cases and 2,005 controls (rs9657904, overall P = 1.60 × 10−10, OR = 1.40). CBLB encodes a negative regulator of adaptive immune responses, and mice lacking the ortholog are prone to experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis.

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Figure 1: Association and linkage disequilibrium patterns at the CBLB locus.

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Acknowledgements

This study was supported by the Fondazione Italiana Sclerosi Multipla (FISM) Cod. 2008/R/7 to F.C., by the Italian Ministry of Scientific Research (MIUR grant 2007KXNKNP) and by US National Institutes of Health contract NO1-AG-1-2109 from National Institute of Aging (NIA) to the SardiNIA ('ProgeNIA') team. The contributions of G.R.A., Y.L. and L.L. were supported in part by NIH grants HG002651, HG005214 and MH084698.

We thank all the cases and controls who made this research possible; J. Todd for a critical revision of the manuscript and helpful suggestions; A. Cao for his continuous help and support; D. Longo, D. Taub, S. Naitza, L. Crisponi, M. Congia, C. Jones, P. Zanella, R. Tirler, L. Leoni, R. Cusano, R. Lampis, V. Orrù, F. Coraddu, J. Foster, M. Luiu, L. Davolio Marani, S. Solveig Fois and M. Arru for help and advice; J. Frau, L. Lorefice, G. Coghe, G. Fenu, L. Mannu, P. Cossu, W. Satta, I. Pirastru, S. Leoni and C. Buscarinu for collaboration in the collection of MS cases; and W. Garau and F. Virdis, along with the personnel of the blood donor centers of Cagliari and Sassari, for their help in the collection of the controls. We are grateful for the important computing resources made available for the imputation and analysis by the CRS4 Computing Cluster in Pula (Cagliari, Italy).

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Author notes

  1. Serena Sanna, Maristella Pitzalis and Magdalena Zoledziewska: These authors contributed equally to this work.

Authors and Affiliations

  1. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Italy

    Serena Sanna, Carlo Sidore, Fabio Busonero, Andrea Maschio, Mariano Dei, Sandra Lai, Antonella Mulas, Gianmauro Cuccuru, Eleonora Porcu, Manuela Uda & Francesco Cucca

  2. Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy

    Maristella Pitzalis, Magdalena Zoledziewska, Francesca Deidda, Fausto Poddie, Laura Morelli, Elisa Deriu & Francesco Cucca

  3. Center for Advanced Studies, Research and Development in Sardinia (CRS4), Laboratorio di Bioinformatica, Parco tecnologico della Sardegna, Pula, Italy

    Ilenia Zara

  4. CRS4, Laboratorio di Genomica, Parco tecnologico della Sardegna, Pula, Italy

    Carlo Sidore, Michael B Whalen, M Francesca Urru & Andrea Angius

  5. Dipartimento di Scienze Neurologiche e Cardiovascolari, Centro Sclerosi Multipla, Università di Cagliari, Cagliari, Italy

    Raffaele Murru, Gianna Costa, Maria Cristina Melis, Loredana Moi, Eleonora Cocco & Maria Giovanna Marrosu

  6. Istituto di Neurologia Clinica, Università di Sassari, Sassari, Italy

    Gabriele Farina, Stefano Sotgiu, Maura Pugliatti & Giulio Rosati

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

    Yun Li, Liming Liang & Gonçalo R Abecasis

  8. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA

    Yun Li

  9. Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA

    Yun Li

  10. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA

    Liming Liang

  11. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

    Liming Liang

  12. Dipartimento di Scienze Biomediche e biotecnologie, Università di Cagliari, Cagliari, Italy

    Patrizia Zavattari

  13. Azienda Ospedaliera Brotzu, Centro Trasfusionale, Cagliari, Italy

    Michele Bajorek

  14. Azienda Sanitaria Locale 1, Sassari, Italy

    Maria Anna Satta

  15. Divisione di Neurologia, Azienda Ospedaliera Brotzu, Cagliari, Italy

    Paola Ferrigno & Maurizio Melis

  16. Divisione Neurologia, Presidio Ospedaliero, Ozieri, Italy

    Sebastiano Traccis

  17. Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA

    David Schlessinger

Authors
  1. Serena Sanna
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  2. Maristella Pitzalis
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  3. Magdalena Zoledziewska
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  4. Ilenia Zara
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  5. Carlo Sidore
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  6. Raffaele Murru
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  7. Michael B Whalen
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  8. Fabio Busonero
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  9. Andrea Maschio
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  10. Gianna Costa
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  11. Maria Cristina Melis
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  14. Laura Morelli
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  15. Gabriele Farina
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  16. Yun Li
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  17. Mariano Dei
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  18. Sandra Lai
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  19. Antonella Mulas
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  20. Gianmauro Cuccuru
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  21. Eleonora Porcu
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  22. Liming Liang
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  23. Patrizia Zavattari
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  24. Loredana Moi
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  25. Elisa Deriu
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  26. M Francesca Urru
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  27. Michele Bajorek
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  28. Maria Anna Satta
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  29. Eleonora Cocco
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  32. Maura Pugliatti
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  33. Sebastiano Traccis
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  34. Andrea Angius
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  35. Maurizio Melis
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  36. Giulio Rosati
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  37. Gonçalo R Abecasis
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  38. Manuela Uda
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  39. Maria Giovanna Marrosu
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  40. David Schlessinger
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  41. Francesco Cucca
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Corresponding author

Correspondence to Francesco Cucca.

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Competing interests

The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Tables 1–3 and Supplementary Figures 1 and 2. (PDF 843 kb)

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Sanna, S., Pitzalis, M., Zoledziewska, M. et al. Variants within the immunoregulatory CBLB gene are associated with multiple sclerosis. Nat Genet 42, 495–497 (2010). https://doi.org/10.1038/ng.584

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