Molecular Medicine

, Volume 21, Issue 1, pp 769–781 | Cite as

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

  • Michael F. Seldin
  • Omar K. Alkhairy
  • Annette T. Lee
  • Janine A. Lamb
  • Jon Sussman
  • Ritva Pirskanen-Matell
  • Fredrik Piehl
  • Jan J. G. M. Verschuuren
  • Anna Kostera-Pruszczyk
  • Piotr Szczudlik
  • David McKee
  • Angelina H. Maniaol
  • Hanne F. Harbo
  • Benedicte A. Lie
  • Arthur Melms
  • Henri-Jean Garchon
  • Nicholas Willcox
  • Peter K. Gregersen
  • Lennart Hammarstrom
Research Article


To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of >6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti-acetylcholine receptor [AChR] antibody positive; onset age ≥50 years) and 2,128 controls matched for sex and population substructure. The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10−7, odds ratio [OR] 1.42) and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10−10, OR 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10−6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases. In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG. Many SNPs within the major histocompatibility complex (MHC) region showed strong associations in LOMG, but with smaller effect sizes than in EOMG (highest OR ∼2 versus ∼6 in EOMG). Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10−12) versus 2.82 in EOMG (P = 3.86 × 10−45). Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs. Conditioning studies of human leukocyte antigen (HLA) amino acid residues also suggest potential functional correlates. Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG.



This work was supported by the National Institutes of Health (NIH/NIAID RO1-AI-68759 to P K Gregersen); by grants from the Palle Ferb Foundation and the Swedish Research Council (to OK Alkhairy and L Hammarstrom); by program grants from the UK Medical Research Council (to N Willcox); by the Prinses Beatrix Fonds (to JJGM Verschuuren); and by grants from the South-Eastern Norwegian Regional Health Authority and the Norwegian Association for Patients with Muscle Diseases (to AH Maniaol). We thank the Norwegian Bone Marrow Registry for control DNAs. We thank the CIDR for providing access to the Health And Retirement Study (HRS) through dbGaP Study Accession: phs000428.v1.p1. We also thank E Bakker in the Department of Human Genetics, Leiden University Medical Center, the Medical Research Council and Myasthenia Gravis Association in the UK, and the many patients and their physicians in all the centers who generously participated in this study.

Supplementary material

10020_2015_2101769_MOESM1_ESM.pdf (1.2 mb)
Supplementary material, approximately 1.21 MB.


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Authors and Affiliations

  • Michael F. Seldin
    • 1
  • Omar K. Alkhairy
    • 2
  • Annette T. Lee
    • 3
  • Janine A. Lamb
    • 4
  • Jon Sussman
    • 5
  • Ritva Pirskanen-Matell
    • 6
  • Fredrik Piehl
    • 6
  • Jan J. G. M. Verschuuren
    • 7
  • Anna Kostera-Pruszczyk
    • 8
  • Piotr Szczudlik
    • 8
  • David McKee
    • 5
  • Angelina H. Maniaol
    • 9
  • Hanne F. Harbo
    • 10
  • Benedicte A. Lie
    • 11
  • Arthur Melms
    • 12
    • 13
  • Henri-Jean Garchon
    • 14
  • Nicholas Willcox
    • 15
  • Peter K. Gregersen
    • 3
  • Lennart Hammarstrom
    • 2
  1. 1.Department of Biochemistry and Molecular Medicine, and Department of MedicineUniversity of CaliforniaDavisUSA
  2. 2.Division of Clinical ImmunologyKarolinska Institutet at Karolinska University Hospital HuddingeStockholmSweden
  3. 3.The Robert S. Boas Center for Genomics and Human GeneticsFeinstein Institute for Medical Research, North Shore-LIJ Health SystemManhassetUSA
  4. 4.Centre for Integrated Genomic Medical Research, Manchester Academic Health Science CentreUniversity of ManchesterManchesterUK
  5. 5.Department of NeurologyGreater Manchester Neuroscience CentreManchesterUK
  6. 6.Department of NeurologyKarolinska University Hospital SolnaStockholmSweden
  7. 7.Department of NeurologyLeiden University Medical CenterLeidenthe Netherlands
  8. 8.Department of NeurologyMedical University of WarsawWarsawPoland
  9. 9.Department of NeurologyOslo University HospitalOsloNorway
  10. 10.Department of NeurologyOslo University Hospital and University of OsloOsloNorway
  11. 11.Department of Medical GeneticsUniversity of Oslo and Oslo University HospitalOsloNorway
  12. 12.Department of NeurologyTübingen University Medical CenterTübingenGermany
  13. 13.Neurologische KlinikUniversitätsklinikum ErlangenErlangenGermany
  14. 14.INSERM U1173University of VersaillesCampus Paris-SaclayFrance
  15. 15.Nuffield Department of Clinical Neurosciences, Weatherall Institute for Molecular MedicineUniversity of OxfordOxfordUK

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