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Original article
Genome-wide significant association with seven novel multiple sclerosis risk loci
  1. Christina M Lill1,2,3,
  2. Felix Luessi2,
  3. Antonio Alcina4,
  4. Ekaterina A Sokolova5,6,
  5. Nerea Ugidos7,8,
  6. Belén de la Hera9,
  7. Léna Guillot-Noël10,
  8. Sunny Malhotra11,
  9. Eva Reinthaler12,
  10. Brit-Maren M Schjeide3,
  11. Julia Y Mescheriakova13,
  12. Andriy Mashychev1,
  13. Inken Wohlers1,
  14. Denis A Akkad14,
  15. Orhan Aktas15,
  16. Iraide Alloza7,8,16,
  17. Alfredo Antigüedad17,
  18. Rafa Arroyo18,
  19. Ianire Astobiza7,8,
  20. Paul Blaschke19,
  21. Alexei N Boyko20,
  22. Mathias Buttmann21,
  23. Andrew Chan22,
  24. Thomas Dörner23,
  25. Joerg T Epplen13,24,
  26. Olga O Favorova25,
  27. Maria Fedetz4,
  28. Oscar Fernández26,
  29. Angel García-Martínez9,
  30. Lisa-Ann Gerdes27,
  31. Christiane Graetz2,
  32. Hans-Peter Hartung15,
  33. Sabine Hoffjan14,
  34. Guillermo Izquierdo28,
  35. Denis S Korobko29,
  36. Antje Kroner21,30,
  37. Christian Kubisch31,
  38. Tania Kümpfel27,
  39. Laura Leyva26,
  40. Peter Lohse32,33,
  41. Nadezhda A Malkova29,34,
  42. Xavier Montalban11,
  43. Ekaterina V Popova20,
  44. Peter Rieckmann21,35,
  45. Alexei S Rozhdestvenskii36,
  46. Christiane Schmied12,
  47. Inna V Smagina37,38,
  48. Ekaterina Y Tsareva25,
  49. Alexander Winkelmann19,
  50. Uwe K Zettl19,
  51. Harald Binder39,
  52. Isabelle Cournu-Rebeix10,
  53. Rogier Hintzen13,
  54. Alexander Zimprich12,
  55. Manuel Comabella11,
  56. Bertrand Fontaine10,40,
  57. Elena Urcelay9,
  58. Koen Vandenbroeck7,8,16,
  59. Maxim Filipenko5,6,
  60. Fuencisla Matesanz4,
  61. Frauke Zipp2,
  62. Lars Bertram1,3,41
  1. 1Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany
  2. 2Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
  3. 3Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
  4. 4Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, Granada, Spain
  5. 5Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Siberian Division, Russian Academy of Sciences, Novosibirsk, Russia
  6. 6Novosibirsk State University, Novosibirsk, Russia
  7. 7Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), Leioa, Spain
  8. 8Achucarro Basque Center for Neuroscience, Zamudio, Spain
  9. 9Immunology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
  10. 10Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM F-75013, Paris, France
  11. 11Department of Neurology-Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya, Cemcat, Hospital Universitari Vall dˊHebron (HUVH), Barcelona, Spain
  12. 12Department of Neurology, Medical University of Vienna, Vienna, Austria
  13. 13Department of Neurology, MS Centre ErasMS, Erasmus Medical Centre, Rotterdam, The Netherlands
  14. 14Department of Human Genetics, Ruhr University, Bochum, Germany
  15. 15Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
  16. 16IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
  17. 17Servicio de Neurología, Hospital Universitario de Basurto, Bilbao, Spain
  18. 18Multiple Sclerosis Unit, Neurology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
  19. 19Department of Neurology, University of Rostock, Rostock, Germany
  20. 20Department of Neurology and Neurosurgery, Pirogov Russian National Research Medical University (RNRMU), Moscow, Russia
  21. 21Department of Neurology, University of Würzburg, Würzburg, Germany
  22. 22Department of Neurology, St. Josef-Hospital, Ruhr-University, Bochum, Germany
  23. 23Department of Medicine, Rheumatology, and Clinical Immunology & DRFZ, Charité University Medicine, Berlin, Germany
  24. 24Faculty of Health, University Witten/Herdecke, Witten, Germany
  25. 25Department of Molecular Biology and Medical Biotechnology, Pirogov Russian National Research Medical University (RNRMU), Moscow, Russia
  26. 26Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain
  27. 27Institute of Clinical Neuroimmunology, Campus Grosshadern, Ludwig Maximilian University, Munich, Germany
  28. 28Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain
  29. 29Multiple Sclerosis Center, Novosibirsk Regional State Clinical Hospital, Novosibirsk, Russia
  30. 30Medical College of Wisconsin, Milwaukee, Wisconsin, USA
  31. 31Institute of Human Genetics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
  32. 32Department of Clinical Chemistry, Ludwig Maximilian University, Munich, Germany
  33. 33CeGaT GmbH, Tuebingen, Germany
  34. 34Department of Clinical Neurology and Algology, Novosibirsk State Medical University, Novosibirsk, Russia
  35. 35Department of Neurology, Sozialstiftung Bamberg Hospital, Bamberg, Germany
  36. 36Department of Neurology of Postgraduate Education, Omsk State Medical Academy, Omsk, Russia
  37. 37Territorial Clinical Hospital, Barnaul, Russia
  38. 38Department of Nervous Diseases, Altai State Medical University, Barnaul, Russia
  39. 39Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany
  40. 40AP-HP, Départment of des Maladies du Système Nerveux, Pitié-Salpêtrère Hospital, Paris, France
  41. 41Department of Medicine, School of Public Health, Imperial College London, London, UK
  1. Correspondence to Dr Christina M Lill, Institute of Neurogenetics, University of Lübeck, Maria-Goeppert-Str. 1, Lübeck 23562, Germany; christina.lill{at}uni-luebeck.de

Abstract

Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors.

Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis.

Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10−8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10−12), CD28 (rs6435203, p=1.35×10−9), LPP (rs4686953, p=3.35×10−8), ETS1 (rs3809006, p=7.74×10−9), DLEU1 (rs806349, p=8.14×10−12), LPIN3 (rs6072343, p=7.16×10−12) and IFNGR2 (rs9808753, p=4.40×10−10). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus.

Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.

  • Genetics
  • Immunology (including allergy)
  • Multiple sclerosis
  • Neurology

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