title: A genome-wide association study of myasthenia gravis.
abstract: OBJECTIVE
  Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood.
  
  
  OBJECTIVE
  To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study.
  
  
  METHODS
  DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication.
  
  
  METHODS
  We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing.
  
  
  RESULTS
  In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases.
  
  
  CONCLUSIONS
  Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.
authors: Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
authors: Alan E
authors: AE
authors: Renton
authors: Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
authors: Hannah A
authors: HA
authors: Pliner
authors: Institute of General Pathology, Catholic University, Rome, Italy.
authors: Carlo
authors: C
authors: Provenzano
authors: Institute of Neurology, Catholic University, Rome, Italy.
authors: Amelia
authors: A
authors: Evoli
authors: Department of Neuroscience, Cisanello Hospital, University of Pisa, Pisa, Italy.
authors: Roberta
authors: R
authors: Ricciardi
authors: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
authors: Michael A
authors: MA
authors: Nalls
authors: Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland6Institute of Medical Genetics, Catholic University, Rome, Italy.
authors: Giuseppe
authors: G
authors: Marangi
authors: Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
authors: Yevgeniya
authors: Y
authors: Abramzon
authors: Genomics Technology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
authors: Sampath
authors: S
authors: Arepalli
authors: Genomics Technology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
authors: Sean
authors: S
authors: Chong
authors: Genomics Technology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
authors: Dena G
authors: DG
authors: Hernandez
authors: Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
authors: Janel O
authors: JO
authors: Johnson
authors: Institute of General Pathology, Catholic University, Rome, Italy.
authors: Emanuela
authors: E
authors: Bartoccioni
authors: Institute of General Pathology, Catholic University, Rome, Italy.
authors: Flavia
authors: F
authors: Scuderi
authors: Department of Neuroscience, Cisanello Hospital, University of Pisa, Pisa, Italy.
authors: Michelangelo
authors: M
authors: Maestri
authors: Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland.
authors: J Raphael
authors: JR
authors: Gibbs
authors: Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland9Rita Levi Montalcini Department of Neuroscience, University of Turin, Tu.
authors: Edoardo
authors: E
authors: Errichiello
authors: Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.
authors: Adriano
authors: A
authors: Chiò
authors: Molecular Genetics Unit, Department of Clinical Pathology, ASO OIRM-S Anna, Turin, Italy.
authors: Gabriella
authors: G
authors: Restagno
authors: Institute of Neurology, Catholic University, Rome, Italy.
authors: Mario
authors: M
authors: Sabatelli
authors: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Mark
authors: M
authors: Macek
authors: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Sonja W
authors: SW
authors: Scholz
authors: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Andrea
authors: A
authors: Corse
authors: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Vinay
authors: V
authors: Chaudhry
authors: Department of Neurology, University of Miami, Miami, Florida.
authors: Michael
authors: M
authors: Benatar
authors: Department of Neurology, University of Kansas Medical Center, Kansas City.
authors: Richard J
authors: RJ
authors: Barohn
authors: Department of Neurology, University of Kansas Medical Center, Kansas City.
authors: April
authors: A
authors: McVey
authors: Department of Neurology, University of Kansas Medical Center, Kansas City.
authors: Mamatha
authors: M
authors: Pasnoor
authors: Department of Neurology, University of Kansas Medical Center, Kansas City.
authors: Mazen M
authors: MM
authors: Dimachkie
authors: Department of Neurology, University of Illinois College of Medicine, Chicago.
authors: Julie
authors: J
authors: Rowin
authors: Department of Neurology, Ohio State University Medical Center, Columbus.
authors: John
authors: J
authors: Kissel
authors: Department of Neurology, Ohio State University Medical Center, Columbus.
authors: Miriam
authors: M
authors: Freimer
authors: Department of Neurology, George Washington University, Washington, DC.
authors: Henry J
authors: HJ
authors: Kaminski
authors: Department of Neurology, Duke University Medical Center, Durham, North Carolina.
authors: Donald B
authors: DB
authors: Sanders
authors: Department of Neurology, Duke University Medical Center, Durham, North Carolina.
authors: Bernadette
authors: B
authors: Lipscomb
authors: Department of Neurology, Duke University Medical Center, Durham, North Carolina.
authors: Janice M
authors: JM
authors: Massey
authors: Department of Neurology, University of North Carolina, Chapel Hill.
authors: Manisha
authors: M
authors: Chopra
authors: Department of Neurology, University of North Carolina, Chapel Hill.
authors: James F
authors: JF
authors: Howard
authors: Department of Clinical Neurosciences, London Health Sciences Centre, London, Ontario, Canada.
authors: Wilma J
authors: WJ
authors: Koopman
authors: Department of Clinical Neurosciences, London Health Sciences Centre, London, Ontario, Canada.
authors: Michael W
authors: MW
authors: Nicolle
authors: Department of Neurology, Indiana University-Purdue University, Indianapolis.
authors: Robert M
authors: RM
authors: Pascuzzi
authors: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors: Alan
authors: A
authors: Pestronk
authors: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors: Charlie
authors: C
authors: Wulf
authors: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors: Julaine
authors: J
authors: Florence
authors: Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada.
authors: Derrick
authors: D
authors: Blackmore
authors: Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada.
authors: Aimee
authors: A
authors: Soloway
authors: Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada.
authors: Zaeem
authors: Z
authors: Siddiqi
authors: Department of Neurology, University at Buffalo SMBS, State University of New York, Buffalo.
authors: Srikanth
authors: S
authors: Muppidi
authors: Department of Neurology, University at Buffalo SMBS, State University of New York, Buffalo.
authors: Gil
authors: G
authors: Wolfe
authors: Department of Neurology, University of California, Davis Medical Center.
authors: David
authors: D
authors: Richman
authors: Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Michelle M
authors: MM
authors: Mezei
authors: Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Theresa
authors: T
authors: Jiwa
authors: Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Joel
authors: J
authors: Oger
authors: Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors: Daniel B
authors: DB
authors: Drachman
authors: Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Research Center, Bethesda, Maryland11Department of Neurology, Johns Hopkins School of Medicine, Baltimore, M.
authors: Bryan J
authors: BJ
authors: Traynor
mesh_terms: D000328:Adult; D017668:Age of Onset; D060908:CTLA-4 Antigen / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D059848:HLA-DQ alpha-Chains / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014481:United States
chemical_list: D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen
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