Abstract

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 × 10−11), IRF8 (P = 3.73 × 10−9) and CD6 (P = 3.79 × 10−9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

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Acknowledgements

P.L.D. is a Harry Weaver Neuroscience Scholar Award of the National MS Society (NMSS); he is also a William C. Fowler Scholar in Multiple Sclerosis Research and is supported by a National Institute of Neurological Disorders and Stroke (NINDS) K08 grant, NS46341. D.A.H. is a Jacob Javits Scholar of the US National Institutes of Health; he is also supported by NINDS P01 AI039671, R01 NS049477, R01NS046630, NMSS Collaborative MS Research Award and NMSS RG3567A. The International MS Genetics Consortium is supported by R01NS049477. L.P. is supported by an NMSS fellowship grant (FG1665-A-1). The genome-wide data on the BWH subjects and the RNA data on MS and CIS subjects from the CLIMB study were generated as part of a collaboration with Affymetrix, Inc. We thank the Myocardial Infarction Genetics Consortium (MIGen) study for the use of their genotype data as control data in our study. The MIGen study was funded by the US National Institutes of Health and National Heart, Lung, and Blood Institute's STAMPEED genomics research program and a grant from the National Center for Research Resources. We acknowledge use of genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. We thank R. Lincoln and R. Gomez for expert specimen management at UCSF as well as A. Santaniello for database management. We thank the Accelerated Cure Project for its work in collecting samples from subjects with MS and for making these samples available to MS investigators. We also thank the following clinicians for contributing to sample collection efforts: Accelerated Cure project, E. Frohman, B. Greenberg, P. Riskind, S. Sadiq, B. Thrower and T. Vollmer; Washington University, B.J. Parks and R.T. Naismith. Finally, we thank the Brigham & Women's Hospital PhenoGenetic Project for providing DNA samples from healthy subjects that were used in the replication effort of this study.

Author information

Author notes

    • Stephen L Hauser
    • , David A Hafler
    •  & Jorge R Oksenberg

    These authors contributed equally to this work.

Affiliations

  1. Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Philip L De Jager
    • , Linda Ottoboni
    • , Susan Romano
    • , Howard L Weiner
    •  & David A Hafler
  2. Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.

    • Philip L De Jager
    • , Linda Ottoboni
    •  & Rebeccah Briskin
  3. Program in Medical & Population Genetics, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Philip L De Jager
    • , Paul I W de Bakker
    • , Linda Ottoboni
    • , Soumya Raychaudhuri
    • , Dong Tran
    • , Cristin Aubin
    • , Mark J Daly
    •  & David A Hafler
  4. Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Xiaoming Jia
    •  & Paul I W de Bakker
  5. Department of Neurology and Institute for Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Joanne Wang
    • , Sergio E Baranzini
    • , Stephen L Hauser
    •  & Jorge R Oksenberg
  6. Institute for Human Genetics, School of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Joanne Wang
    • , Stephen L Hauser
    •  & Jorge R Oksenberg
  7. Rush Alzheimer Disease Center & Department of Neurological Sciences, Rush University, Chicago, Illinois, USA.

    • Neelum T Aggarwal
    •  & Denis Evans
  8. Department of Neurology, Washington University, St. Louis, Missouri, USA.

    • Laura Piccio
    •  & Anne H Cross
  9. Division of Immunology, Allergy and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Soumya Raychaudhuri
  10. Miami Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, Florida, USA.

    • Jacob L McCauley
    •  & Margaret A Pericak-Vance
  11. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • Jonathan L Haines
  12. GlaxoSmithKline Clinical Imaging Centre, Hammersmith Hospital and Department of Clinical Neurosciences, Imperial College, London.

    • Rachel A Gibson
    •  & Paul M Matthews
  13. Department of Neurology, University Hospital Basel, Basel, Switzerland.

    • Yvonne Naeglin
    •  & Ludwig Kappos
  14. Department of Neurology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands.

    • Bernard Uitdehaag
    •  & Chris Polman
  15. Department of Social Medicine, University of Bristol, Bristol, UK.

    • Wendy L McArdle
  16. Division of Community Health sciences, St. George's, University of London, London, UK.

    • David P Strachan
  17. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Mark J Daly
  18. University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, UK.

    • Alastair Compston
    •  & Stephen J Sawcer

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Contributions

P.L.D., D.A.H., S.L.H., P.M.M. and J.R.O. designed the study. P.L.D. and J.R.O. wrote the manuscript. P.I.W.d.B., P.L.D., S.R., M.J.D., D.T., J.W., S.E.B. and X.J. performed analytical work. P.I.W.d.B., X.J. and M.J.D. developed the meta-analysis method while S.R. developed the subject matching algorithm. L.O. and P.L.D. performed the quality control analysis and quantitative trait analysis of the RNA from MS PBMC samples. C.A. generated and processed genotype data for analysis. P.L.D., N.T.A., L.P., R.B., R.A.G., P.M.M., Y.N., L.K., B.U., C.P., W.L.M., D.P.S., D.E., A.H.C., A.C., S.J.S., H.L.W., S.L.H., J.R.O. and D.A.H. contributed to DNA sample collection and genetic data. J.L.M., M.A.P.-V. and J.L.H. contributed to the interpretation of the results. All authors have read and contributed to the manuscript.

Corresponding author

Correspondence to Philip L De Jager.

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DOI

https://doi.org/10.1038/ng.401

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