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IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

Genes & Immunity volume 11, pages 397–405 (2010)Cite this article

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Abstract

A recent meta-analysis identified seven single-nucleotide polymorphisms (SNPs) with suggestive evidence of association with multiple sclerosis (MS). We report an analysis of these polymorphisms in a replication study that includes 8,085 cases and 7,777 controls. A meta-analysis across the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value=3.55 × 10−9), IL12A (P=3.08 × 10−8) and MPHOSPH9/CDK2AP1 (P=3.96 × 10−8). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P=1.18 × 10−5) and in peripheral blood mononuclear cells from subjects with MS (P=0.01). Thus, we report three new MS susceptibility loci, including a novel inflammatory disease locus that could affect autoreactive cell proliferation.

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Acknowledgements

We are grateful to the patients and the healthy controls for their participation in this study. PLD is a Harry Weaver Neuroscience Scholar Award Recipient of the National MS Society (NMSS). DAH is a Jacob Javits Scholar of NIH. SD is supported by a FISM grant (2008/R/11). BF and IR are authors on behalf of REFGENSEP, a national French clinical and research network funded by INSERM, ARSEP and AFM. The International MS Genetics Consortium is supported by R01NS049477 and by the National Multiple Sclerosis Society. This work was also supported by the Medical Research Council (G0700061) and by the Cambridge NIHR Biomedical Research Centre. The sampling and analysis of the Swedish cohorts have received grant support from The Swedish Research Council, the EU fp6 program neuropromise (LSHM-CT-2005-018637), as well as from the Bibbi and Niels Jensens Foundation, The Montel Williams Foundation and the Söderberg Foundation.

Author information

Author notes

  1. Members of the International Multiple Sclerosis Genetics Consortium are listed in the Appendix.

  2. Dr PL De Jager, Department of Neurology, Brigham & Women's Hospital, Program in NeuroPsychiatric Genomics, 77 Avenue Louis Pasteur, NRB168, Boston, MA 02115, USA. E-mail: pdejager@rics.bwh.harvard.edu

Authors and Affiliations

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    The International Multiple Sclerosis Genetics Conssortium (IMSGC)

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    The authors declare no conflict of interest.

    Additional information

    Web Resources

    The URLs for data presented herein are as follows:

    International HapMap Project, http://hapmap.ncbi.nlm.nih.gov/

    GENe Expression VARiation, http://www.sanger.ac.uk/humgen/genevar/

    meta: Meta-Analysis, R package http://CRAN.R-project.org/package=meta

    rmeta: Meta-Analysis, R package http://CRAN.R-project.org/package=rmeta

    ‘mRNA-by-SNP-browser’ v1.0.1, http://www.sph.umich.edu/csg/liang/asthma/

    The Gene Expression Omnibus accession number for the RNA data obtained from PBMCs and reported in this paper is GSE16214.

    Supplementary Information accompanies the paper on Genes and Immunity website

    Supplementary information

    Appendix

    Appendix

    Members of the International Multiple Sclerosis Genetics Consortium

    F Esposito1,2, NA Patsopoulos3,4,5, S Cepok6, I Kockum7,8, V Leppä9,10, DR Booth11, RN Heard11, GJ Stewart11, M Cox12, RJ Scott12, J Lechner-Scott12, A Goris13, R Dobosi13, B Dubois13, JD Rioux14,15, AB Oturai16, HB Søndergaard16, F Sellebjerg16, PS Sørensen16, M Reunanen17, K Koivisto18, I Cournu-Rebeix19,20,21, B Fontaine19,20,21, J Winkelmann22,23,24, C Gieger25, C Infante-Duarte26, F Zipp27, L Bergamaschi28, M Leone29, R Bergamaschi30, P Cavalla31, ÅR Lorentzen32,33, I-L Mero33,34, EG Celius34, HF Harbo32,34, A Spurkland35, M Comabella36, B Brynedal7, L Alfredsson37, L Bernardinelli38,39, NP Robertson40, CP Hawkins41,42, LF Barcellos43, G Beecham44, W Bush45, BAC Cree46, MJ Daly4,47,48, AJ Ivinson49, C Aubin48, A Compston50, S D’Alfonso28, JL Haines45, SL Hauser46, B Hemmer6, J Hillert8,37, JL McCauley44, J Oksenberg46, T Olsson7,8, A Palotie9,10, L Peltonen9,10,51, MA Pericak-Vance44, J Saarela9,10, SJ Sawcer50, B Stranger3,4,48, FM Boneschi1,2, G Comi1,2, DA Hafler4,48,52, PIW de Bakker3,4,48 and PL De Jager4,5,48, International Multiple Sclerosis Genetics Consortium members.

    1Department of Neurology, Scientific Institute San Raffaele, Milan, Italy; 2Institute of Experimental Neurology, Scientific Institute San Raffaele, Milan, Italy; 3Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA; 4Harvard Medical School, Boston, MA, USA; 5Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham & Women's Hospital, Boston, MA, USA; 6Klinikum rechts der Isar, Technische Universität, Münch, Germany; 7Neuroimmunology Unit, Department of clinical neuroscience, Karolinska Institutet at Karolinska University Hospital, Solna, Sweden; 8Center for Molecular Medicine, Karolinska Institutet at Karolinska University Hospital, Solna, Sweden; 9Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland; 10Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; 11University of Sydney, Institute for Immunology and Allergy Research, Westmead Millennium Institute, Westmead Hospital, NSW, Australia; 12University of Newcastle, Callaghan, NSW Australia; 13Section for Experimental Neurology, Katholieke Universiteit Leuven, Leuven, Belgium; 14Université de Montréal, Montréal, Québec, Canada; 15Montreal Heart Institute, H1 T 1C8, Montréal, Québec, Canada; 16The Danish Multiple Sclerosis Research Center, Copenhagen University Hospital, Rigshospitalet, DK-2100, Copenhagen, Denmark; 17Department of Neurology, Oulu University Hospital, Oulu, Finland; 18Central Hospital of Seinäjoki, Seinäjoki, Finland; 19INSERM, UMR_S975, Paris, France; 20UPMC Univ Paris 06, UMR_S975, Centre de Recherche Institut du Cerveau et de la Moelle, CNRS 7225, Paris, France; 21Département de Neurologie, Pitié –Salpêtrière Hospital, AP-HP, 75651 Paris, France; 22Klinik für Neurologie, Technische Universität München, München, Deutsch; 23Institut für Humangenetik, Technische Universität München, München, Deutsch; 24Institut für Humangenetik, Helmholtz Zentrum München, München, Deutsch; 25Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Munich, Germany; 26Charite-Universitaetsmedizin Berlin, Cecilie Vogt Clinic for Neurology, Berlin, Germany; 27Department of Neurology, University Medicine Mainz, Johannes Gutenberg University, Mainz, Germany; 28Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases, University of Eastern Piedmont, Novara, Italy; 29Clinica Neurologica, AOU Maggiore della Carità, Novara, Italy; 30Neurological Institute C. Mondino, IRCCS, Pavia, Italy; 31Department of Neurology, Ospedale San Giovanni Battista, Torino, Italy; 32Department of Neurology, Faculty Division Ullevål University Hospital, University of Oslo, Oslo, Norway; 33Institute of Immunology, Rikshospitalet, Oslo University Hospital, Oslo, Norway; 34Department of Neurology, Oslo University Hospital, Ullevål, Oslo, Norway; 35Institute of Basal Medical Sciences, University of Oslo, Blindern, Oslo, Norway; 36Unitat de Neuroimmunologia Clínica, CEM-Cat, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 37Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 38University of Pavia, Department of Applied Sciences, Pavia, Italy; 39University of Cambridge, Statistical Laboratory, Centre for Mathematical Sciences, Wilberforce Road, Cambridge, UK; 40Department of Neurology, University Hospital of Wales, Heath Park, Cardiff, UK; 41Human Genomics research group, Keele University, Stoke-on-Trent, UK; 42Department of Neurology, University Hospital North Staffordshire, Stoke-on-Trent, UK; 43Division of Epidemiology, School of Public Health, University of California at Berkeley, Berkeley, CA, USA; 44John P. Hussman Institute for Human Genomics, The University of Miami Miller School of Medicine, Miami, FL, USA; 45Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA; 46Department of Neurology, University of California San Francisco, San Francisco, CA, USA; 47Massachusetts General Hospital, Boston, MA, USA; 48Program in Medical & Population Genetics, Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA; 49Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, USA; 50University of Cambridge, Department of Clinical Neuroscience, Addenbrooke's Hospital, Cambridge, UK; 51The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK and 52Department of Neurology, Yale University Medical School, New Haven, CT, USA.

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    The International Multiple Sclerosis Genetics Conssortium (IMSGC). IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes Immun 11, 397–405 (2010). https://doi.org/10.1038/gene.2010.28

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