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Closing the case of APOE in multiple sclerosis: no association with disease risk in over 29 000 subjects
  1. Christina M Lill1,2,
  2. Tian Liu2,3,
  3. Brit-Maren M Schjeide2,
  4. Johannes T Roehr2,
  5. Denis A Akkad4,
  6. Vincent Damotte5,
  7. Antonio Alcina6,
  8. Miguel A Ortiz7,
  9. Rafa Arroyo8,
  10. Aitzkoa Lopez de Lapuente9,
  11. Paul Blaschke10,
  12. Alexander Winkelmann10,
  13. Lisa-Ann Gerdes11,
  14. Felix Luessi1,
  15. Oscar Fernadez12,
  16. Guillermo Izquierdo12,
  17. Alfredo Antigüedad13,
  18. Sabine Hoffjan4,
  19. Isabelle Cournu-Rebeix5,14,
  20. Silvana Gromöller2,
  21. Hans Faber15,
  22. Maria Liebsch2,
  23. Esther Meissner2,
  24. Coralie Chanvillard16,
  25. Emmanuel Touze17,
  26. Fernando Pico18,
  27. Philippe Corcia19 ANZgene Consortium,,
  28. Thomas Dörner20,
  29. Elisabeth Steinhagen-Thiessen21,
  30. Lars Baeckman22,
  31. Hauke R Heekeren3,23,
  32. Shu-Chen Li3,
  33. Ulman Lindenberger3,
  34. Andrew Chan24,
  35. Hans-Peter Hartung25,
  36. Orhan Aktas25,
  37. Peter Lohse26,
  38. Tania Kümpfel11,
  39. Christian Kubisch27,
  40. Joerg T Epplen4,
  41. Uwe K Zettl10,
  42. Bertrand Fontaine5,12,
  43. Koen Vandenbroeck9,28,
  44. Fuencisla Matesanz6,
  45. Elena Urcelay8,
  46. Lars Bertram2,
  47. Frauke Zipp1,
  1. 1Deptartment of Neurology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
  2. 2Deptartment of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
  3. 3Max Planck Institute for Human Development, Berlin, Germany
  4. 4Department of Human Genetics, Ruhr University, Bochum, Germany
  5. 5INSERM-CNRS-UPMC-ICM, UMR 975-7225, Institut cerveau Moelle, Hopital Pitié-Salpêtrière, Paris, France
  6. 6Institution Parasitología y Biomedicina ‘López Neyra’, CSIC, Granada, Spain
  7. 7Inmunología Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
  8. 8Multiple Sclerosis Unit, Neurology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
  9. 9Neurogenomiks Laboratory, Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Spain
  10. 10Department of Neurology, University of Rostock, Rostock, Germany
  11. 11Institute for Clinical Neuroimmunology, Ludwig Maximilian University, Munich, Germany
  12. 12Unidad de Esclerosis Múltiple, Hospital Virgen Macarena, Sevilla, Spain
  13. 13Servicio de Neurología, Hospital de Basurto, Bilbao, Spain
  14. 14Department of Neurology, Hopital Pitié-Salpêtrière, Paris, France
  15. 15Section of Neurology, Max Planck Institute for Psychiatry, Munich, Germany
  16. 16Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany
  17. 17Department of Neurology, Hôpital Sainte-Anne, Paris, France
  18. 18Department of Neurology, Centre Hospitalier de Versailles, Le Chesnay, France
  19. 19Department of Neurology, Centre Hospitalier Regional Universitaire, Tours, France
  20. 20Department of Medicine, Rheumatology, and Clinical Immunology, Charité University Medicine, Berlin, Germany
  21. 21Interdisciplinary Metabolic Center, Lipids Clinic, Charité University Medicine, Berlin, Germany
  22. 22Aging Research Center, Karolinska Institute, Stockholm, Sweden
  23. 23Department of Education and Psychology, Free University, Berlin, Germany
  24. 24Department of Neurology, Ruhr University, Bochum, Germany
  25. 25Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
  26. 26Department of Clinical Chemistry, Ludwig Maximilian University, Munich, Germany
  27. 27Institute of Human Genetics, University of Ulm, Ulm, Germany
  28. 28IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
  1. Correspondence to Professor Frauke Zipp, Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University Center Mainz, Neurology Department, Langenbeckstr. 1, Mainz 55131, Germany; frauke.zipp{at}


Background Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently.

Methods We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments.

Results Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively).

Conclusion Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.

  • Multiple sclerosis
  • APOE
  • meta-analysis
  • genome-wide association study
  • imputation

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