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Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

Nature Genetics volume 41, pages 776–782 (2009)Cite this article

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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Figure 1: Enrichment of associations in the replication stage that are consistent with the meta-analysis.
Figure 2: Three previously unidentified loci, TNFRSF1A, IRF8 and CD6, with genome-wide level of evidence of association to MS.
Figure 3: Interferon response genes are coordinately upregulated relative to the rs17445836[G] allele of IRF8.

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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

  1. Stephen L Hauser, David A Hafler and Jorge R Oksenberg: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Immunology, Department of Neurology, Center for Neurologic Diseases, 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, Department of Medicine, Allergy and Rheumatology, 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. Hammersmith Hospital and Department of Clinical Neurosciences, GlaxoSmithKline Clinical Imaging Centre, 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. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

    Alastair Compston & Stephen J Sawcer

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International MS Genetics Consortium

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.

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Correspondence to Philip L De Jager.

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De Jager, P., Jia, X., Wang, J. et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 41, 776–782 (2009). https://doi.org/10.1038/ng.401

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