Genome-Wide Association Study of Myasthenia Gravis

The purpose of this project was to conduct a genome-wide associate study to search for the genetic factors that predispose to myasthenia gravis. The rationale for this study lies in the fact that, although the immunological and physiological processes affecting the neuromuscular junctions of myasthenia gravis patients are well understood, the spectrum of genetic factors that predispose to myasthenia gravis and influence its disease manifestations are not well known. Identification of the myasthenia gravis-related genes will shed light on the fundamental cellular events underlying myasthenia gravis, and will provide focus for research aimed at developing therapies that alter the natural course of the disease.

A consortium of fourteen institutions in North America collected DNA samples from 1028 people diagnosed with autoimmune myasthenia gravis. Relevant clinical data have been collected for each patient, including age of onset, severity of disease, response to drug therapy, personal and family history of other autoimmune diseases. Genotyping of the case cohort was performed in the Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD. Genotyping of the case cohort was performed using the HumanOmniExpress-12v1_C SNP array manufactured by Illumina Inc. For the control cohort, we downloaded genotype data from dbGAP (accession phs000196.v2.p1) for 1,998 US neurologically normal individuals. The control cohort had been previously genotyped at the Center for Inherited Disease Research at Johns Hopkins University on HumanOmni1-Quad version 1.0B beadchips (Illumina) as part of the NeuroGenetics Research Consortium GWAS of Parkinson's disease. Analyses were confined to the 677,673 autosomal SNPs that were common to both chips.

Of the 1028 samples which were genotyped, 21 samples were excluded due to mismatched genders, 9 were excluded due to low genotype call rate, 5 samples were excluded as duplicates, and 25 samples were excluded as ethnic outliers. The remaining 972 samples were used in analysis.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 972
• Subject Sample Telemetry Report (SSTR)

• BioProject
• BioSample
• MeSH

• Diagnosed as having myasthenia gravis by a neurologist specializing in myasthenia gravis.

• Positive AChR antibody titer.

• Onset of symptoms after 18 years of age.

• Non-Hispanic Caucasian ethnicity.

• Positive test results for antibody to anti-muscle-specific kinase (anti-MuSK).

Case cohort genotype data submitted to dbGaP in March 2014.

• Primary Phenotype: Myasthenia gravis

• Principal Investigators
  • Bryan J. Traynor, PhD, M.D. National Institutes of Health, Bethesda, MD, USA.
  • Daniel B. Drachman, M.D. Johns Hopkins University, Baltimore, MD, USA.
• Co-Investigators
  • Alan E. Renton. Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Hannah A. Pliner. Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Carlo Provenzano. Institute of General Pathology, Catholic University, Rome, Italy.
  • Amelia Evoli. Institute of Neurology, Catholic University, Rome, Italy.
  • Michael A. Nalls. Molecular Genetics Section, Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Giuseppe Marangi. Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA; Institute of Medical Genetics, Catholic University, Rome, Italy.
  • Yevgeniya Abramzon. Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Sampath Arepalli. Genomics Technology Group, Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Sean Chong. Genomics Technology Group, Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Dena G. Hernandez. Genomics Technology Group, Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Emanuela Bartoccioni. Institute of General Pathology, Catholic University, Rome, Italy.
  • Flavia Scuderi. Institute of General Pathology, Catholic University, Rome, Italy.
  • Roberta Ricciardi. Department of Neuroscience, Cisanello Hospital, University of Pisa, Pisa, Italy.
  • Michelangelo Maestri. Department of Neuroscience, Cisanello Hospital, University of Pisa, Pisa, Italy.
  • J. Raphael Gibbs. Computational Biology Core, Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Edoardo Errichiello. Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA; 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy.
  • Adriano Chiò. 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy.
  • Gabriella Restagno. Molecular Genetics Unit, Department of Clinical Pathology, A.S.O. O.I.R.M.-S. Anna, Turin, Italy.
  • Mario Sabatelli. Mario Sabatelli Institute of Neurology, Catholic University, Rome, Italy.
  • Michael Benatar. Department of Neurology, University of Miami Health System, Miami, FL, USA.
  • Richard Barohn. Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
  • Mazen Demachkie. Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
  • Julie Rowin. Department of Neurology, University of Illinois College of Medicine, Chicago, IL, USA.
  • John Kissel. Department of Neurology, Ohio State University Medical Center, Columbus, OH, USA.
  • Miriam Freimer. Department of Neurology, Ohio State University Medical Center, Columbus, OH, USA.
  • Henry J. Kaminski. Department of Neurology, George Washington University, Washington, DC, USA.
  • Don B. Sanders. Department of Neurology, Duke University Medical Center, Durham, NC, USA.
  • Janice M. Massey. Department of Neurology, Duke University Medical Center, Durham, NC, USA.
  • James F. Howard Jr. Department of Neurology, Duke University Medical Center, Durham, NC, USA.
  • Michael W. Nicolle. Department of Neurology, London Health Sciences Centre, London, ON, Canada.
  • Robert M. Pascuzzi. Department of Neurology, Indiana University-Purdue University, Indianapolis, IN, USA.
  • Alan Pestronk. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
  • Julaine Florence. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
  • Zaeem Siddiqi. Department of Medicine, University of Alberta Hospital, Edmonton, AB, Canada.
  • Gil Wolfe. Department of Neurology, University at Buffalo SMBS, State University of New York, Buffalo, NY, USA.
  • David Richman. Department of Neurology, UC Davis Medical Center, Davis, CA, USA.
  • Joel Oger. Department of Neurology, Vancouver Coastal Health, Vancouver, BC, Canada.
  • Janel Johnson. Neuromuscular Diseases Research Unit, Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD, USA.
  • Bernadette Lipscomb. Department of Neurology, Duke University Medical Center, Durham, NC, USA.
  • Manisha Chopra. Department of Neurology, UNC Chapel Hill, Chapel Hill, NC, USA.
  • Wilma J. Koopman. Department of Neurology, London Health Sciences Centre, London, ON, Canada.
  • Charlie Wulf. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
  • Derrick Blackmore. Department of Medicine, University of Alberta Hospital, Edmonton, AB, Canada.
  • Aimee Soloway. Department of Medicine, University of Alberta Hospital, Edmonton, AB, Canada.
  • Srikanth Muppidi. Department of Neurology, University at Buffalo SMBS, State University of New York, Buffalo, NY, USA.
  • Michele Mezei. Department of Neurology, Vancouver Coastal Health, Vancouver, BC, Canada.
  • Theresa Jiwa. Department of Neurology, Vancouver Coastal Health, Vancouver, BC, Canada.
  • Mark Macek. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Sonja W. Scholz. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Andrea Corse. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Vinay Chaudhry. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
• Funding Sources
  • Myasthenia Gravis Foundation, New York, NY, USA.
  • Bequest from Geraldine Weinrib.
  • Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.