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Genome-wide significant association of ANKRD55 rs6859219 and multiple sclerosis risk
  1. Christina M Lill1,2,
  2. Brit-Maren M Schjeide1,
  3. Christiane Graetz1,2,
  4. Tian Liu3,
  5. Vincent Damotte4,
  6. Denis A Akkad5,
  7. Paul Blaschke6,
  8. Lisa-Ann Gerdes7,
  9. Antje Kroner8,9,
  10. Felix Luessi2,
  11. Isabelle Cournu-Rebeix4,10,
  12. Sabine Hoffjan5,
  13. Alexander Winkelmann6,
  14. Emmanuel Touze11,
  15. Fernando Pico12,
  16. Philippe Corcia13,
  17. David Otaegui14,
  18. Alfredo Antigüedad15,
  19. Antonio Alcina16,
  20. Manuel Comabella17,
  21. Xavier Montalban17,
  22. Javier Olascoaga18,
  23. Fuencisla Matesanz16,
  24. Thomas Dörner19,
  25. Shu-Chen Li3,20,
  26. Elisabeth Steinhagen-Thiessen21,
  27. Ulman Lindenberger3,
  28. Andrew Chan22,
  29. Peter Rieckmann8,23,
  30. Hans-Peter Hartung24,
  31. Orhan Aktas24,
  32. Peter Lohse25,
  33. Mathias Buttmann8,
  34. Tania Kümpfel7,
  35. Christian Kubisch26,
  36. Uwe K Zettl6,
  37. Joerg T Epplen5,
  38. Bertrand Fontaine4,10,
  39. Frauke Zipp2,
  40. Koen Vandenbroeck27,28,
  41. Lars Bertram1
  1. 1Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany
  2. 2Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
  3. 3Max Planck Institute for Human Development, Berlin, Germany
  4. 4UPMC-INSERM-CNRS-UPMC-ICM, UMR 975–7225, Institut Cerveau Moelle Epinière (ICM), Hôpital Pitié-Salpêtrière, Paris, France
  5. 5Department of Human Genetics, Ruhr University, Bochum, Germany
  6. 6Department of Neurology, University of Rostock, Rostock, Germany
  7. 7Institute for Clinical Neuroimmunology, Ludwig Maximilian University, Munich, Germany
  8. 8Department of Neurology, University of Würzburg, Würzburg, Germany
  9. 9Centre for Research in Neuroscience at McGill University, Montreal, Canada
  10. 10Assistance Publique-Hôpitaux de Paris (AP-HP), Département de Neurologie, Hôpital Pitié-Salpêtrière, Paris, France
  11. 11Department of Neurology, Hôpital Sainte-Anne, Paris, France
  12. 12Department of Neurology, Centre Hospitalier de Versailles, Le Chesnay, France
  13. 13Department of Neurology, Centre Hospitalier Regional Universitaire, Tours, France
  14. 14Área de Neurociencias, Inst. Investigación Sanitaria Biodonostia, San Sebastián, Spain
  15. 15Servicio de Neurología, Hospital de Basurto, Bilbao, Spain
  16. 16Department of Biología Celular e Inmunología, Instituto de Parasitología y Biomedicina ‘LópezNeyra’ (IPBLN), CSIC, Granada, Spain
  17. 17Centre d'Esclerosi Múltiple de Catalunya, CEMCat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron, Barcelona, Spain
  18. 18Servicio de Neurología, Unidad de Esclerosis Múltiple, Hospital Donostia, San Sebastián, Spain
  19. 19Department of Medicine, Rheumatology, and Clinical Immunology & DRFZ, Charité University Medicine, Berlin, Germany
  20. 20Department of Psychology, Technische Universität Dresden, Dresden, Germany
  21. 21Interdisciplinary Metabolic Center, Lipids Clinic, Charité University Medicine, Berlin, Germany
  22. 22Department of Neurology, St. Josef-Hospital, Ruhr-University, Bochum, Germany
  23. 23Department of Neurology, Sozialstiftung Bamberg Hospital, Bamberg, Germany
  24. 24Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
  25. 25Department of Clinical Chemistry, Ludwig Maximilian University, Munich, Germany
  26. 26Institute of Human Genetics, University of Ulm, Ulm, Germany
  27. 27Neurogenomiks Laboratory, Department of Neuroscience, University of the Basque Country UPV/EHU, Leioa, Spain
  28. 28IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
  1. Correspondence to Dr Christina M Lill, Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Ihnestr. 63-73, 14195 Berlin, Germany; lill{at}

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Multiple sclerosis (MS) is a genetically complex disease that shares a substantial proportion of risk loci with other autoimmune diseases.1 Along these lines, ANKRD55, originally implicated in rheumatoid arthritis, was recently reported as a potential novel MS risk gene (rs6859219, p=1.9×10−7).2 Here, we comprehensively validated this effect in independent datasets comprising 8846 newly genotyped subjects from Germany and France as well as 5003 subjects from two genome-wide association studies (GWAS). Upon meta-analysis of all available data (19 686 subjects), ANKRD55 rs6859219 now shows compelling evidence for association with MS at genome-wide significance (OR=1.19, p=3.1×10−11). Our study adds ANKRD55 to the list of established MS risk loci and extends previous evidence suggesting an overlapping genetic foundation across autoimmune diseases.

Ankyrin repeats are abundant in a large number of different proteins in humans and mediate protein–protein interactions. DNA-sequence variants in ankyrin repeat domain-containing proteins have been linked to a wide range of diseases; for example, KRIT1 mutations causative for cerebral cavernous malformations,3 NOTCH3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and RFXANK mutations in the bare lymphocyte syndrome.4 ANKRD55 (located on chromosome 5q11.2) encodes the ‘ankyrin repeat domain-containing protein 55’ the function of which is currently unknown. Single nucleotide polymorphism rs6859219 in ANKRD55 was implicated in a recent GWAS meta-analysis on rheumatoid arthritis.5 Furthermore, a joint analysis of datasets on rheumatoid arthritis and coeliac disease also indicated a role of ANKRD55 in the latter.6 Given the augmenting evidence suggesting an overlap in the genetic architecture of autoimmune diseases including MS, we have previously investigated 10 ‘autoimmune loci’ in 2895 Spanish MS cases and 2942 controls.2 In that study, rs6859219 emerged as a putative new MS locus albeit at subgenome-wide significance (p=1.9×10−7).2 Our failure to establish …

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  • Contributors Study design and supervision: CML, FZ, KV and LB. Data acquisition and performing of experiments: CML, B-MMS, CG, VD, DAA, PB, L-AG, AK, FL, IC-R, SH, AW, ET, FP, PC, DO, AAn, AAl, MC, XM, JO, FM, TD, S-CL, ES-T, UL, AC, PR, H-PH, OA, PL, MB, TK, CK, UKZ, JTE and BF. Data analysis and interpretation of results: CML, TL, KV and LB. Writing of manuscript: CML and LB with the help of all coauthors.

  • Funding This project was funded by grants from the German Ministry for Education and Research (BMBF) and German Research Foundation (DFG; to FZ), the BMBF and the Cure Alzheimer's Fund (to LB), the Walter- and Ilse-Rose-Stiftung (to H-PH and OA), the BMBF (grant NBL3 to UKZ; grant 01UW0808 to UL and ES-T), and the Innovation Fund of the Max Planck Society (M.FE.A.BILD0002 to UL). This project was supported by INSERM, ARSEP, AFM and GIS-IBISA. CML was supported by the Fidelity Biosciences Research Initiative.

  • Competing interests LA Gerdes reports to have received travel expenses and personal compensation from Merck Serono, Teva Pharmaceutical Industries, Bayer Schering Pharma, Novartis and Biogen Idec. T Kl reports to have received travel expenses and personal compensations from Bayer Schering Pharmacy, Teva, Merck-Serono, Novartis, Sanofi-Aventis and Biogen-Idec as well as grant support from Bayer-Schering AG. None of the other authors reports any disclosures.

  • Provenance and peer review Not commissioned; externally peer reviewed.