Article Text

Download PDFPDF
Original research
Myasthenia gravis genome-wide association study implicates AGRN as a risk locus
  1. Apostolia Topaloudi1,
  2. Zoi Zagoriti2,
  3. Alyssa Camille Flint1,
  4. Melanie Belle Martinez1,
  5. Zhiyu Yang1,
  6. Fotis Tsetsos3,
  7. Yiolanda-Panayiota Christou4,
  8. George Lagoumintzis2,
  9. Evangelia Yannaki5,
  10. Eleni Zamba-Papanicolaou4,6,
  11. John Tzartos7,
  12. Xanthippi Tsekmekidou8,
  13. Kalliopi Kotsa8,
  14. Efstratios Maltezos9,
  15. Nikolaos Papanas9,
  16. Dimitrios Papazoglou9,
  17. Ploumis Passadakis10,
  18. Athanasios Roumeliotis11,
  19. Stefanos Roumeliotis11,
  20. Marios Theodoridis10,
  21. Elias Thodis10,
  22. Stylianos Panagoutsos10,
  23. John Yovos8,
  24. John Stamatoyannopoulos12,
  25. Konstantinos Poulas2,
  26. Kleopas Kleopa4,13,
  27. Socrates Tzartos2,14,
  28. Marianthi Georgitsi15,
  29. Peristera Paschou1
  1. 1 Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA
  2. 2 Department of Pharmacy, University of Patras, Rio, Greece
  3. 3 Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece
  4. 4 The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
  5. 5 Department of Hematology, George Papanicolaou Hospital, Thessaloniki, Greece
  6. 6 Department of Neuroepidemiology and Centre for Neuromuscular Disorders, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus
  7. 7 Tzartos NeuroDiagnostics, Athens, Greece
  8. 8 Division of Endocrinology and Metabolism-Diabetes Center, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
  9. 9 Diabetes Center, 2nd Department of Internal Medicine, Alexandroupolis University General Hospital, Democritus University of Thrace, Alexandroupoli, Greece
  10. 10 Department of Nephrology, Alexandroupolis University General Hospital, Democritus University of Thrace, Alexandroupoli, Greece
  11. 11 Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
  12. 12 Departments of Medicine and Genome Sciences, University of Washington, Seattle, Washington, USA
  13. 13 Department of Neuroscience and Centre for Neuromuscular Disorders, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus
  14. 14 Hellenic Pasteur Institute, Athens, Greece
  15. 15 1st Laboratory of Medical Biology-Genetics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
  1. Correspondence to Dr Peristera Paschou, Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA; ppaschou{at}purdue.edu; Dr Marianthi Georgitsi, 1st Laboratory of Medical Biology-Genetics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; margeorgitsi{at}auth.gr

Abstract

Background Myasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date.

Methods We performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders.

Results We confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10−13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders.

Discussion Our gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms.

  • autoimmune diseases
  • human genetics
  • neuromuscular diseases

Data availability statement

Data are available in a public, open access repository. Data are available upon reasonable request. Summary statistics will become available upon publication of this study at the Paschou Lab website. De-identified raw genotype data can become available upon request by email to the corresponding author (ppaschou@purdue.edu).

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data are available in a public, open access repository. Data are available upon reasonable request. Summary statistics will become available upon publication of this study at the Paschou Lab website. De-identified raw genotype data can become available upon request by email to the corresponding author (ppaschou@purdue.edu).

View Full Text

Footnotes

  • MG and PP are joint senior authors.

  • MG and PP contributed equally.

  • Contributors PPasc and MG conceived and designed the study. PPasc, MG, AT, ZZ and FT acquired the samples and data. PPasc, AT, ACF, MBM, FT and ZY analysed the data. PPasc, MG, ZZ, FT, Y-PC, GL, EY, EZ-P, JT, KKo, EM, SP, NP, DP, PPass, AR, MT, ET, XT, JY, JS, KP, KKl and ST contributed to data acquisition, sample collection and clinical characterisation. All authors contributed to drafting the manuscript and provided critical comments and revisions.

  • Funding This work was supported by NSF award #1715202, the European Social Fund, and Greek funds through the National Strategic Reference Framework (NSRF) THALES Programme 2012–2015 and the NSRF ARISTEIA II Programme 2007–2013 to PPasc, and grants from the Association Francaise contre les Myopathies (AFM, grant no 80077) to ST.

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.