A Multicenter Study of BRD2 as a Risk Factor for Juvenile Myoclonic Epilepsy

Authors

  • Gianpiero L. Cavalleri,

    1. The Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, and Division of Neurology, Beaumont Hospital, Dublin, Ireland
    Search for more papers by this author
  • Nicole M. Walley,

    1. The Institute for Genome Science and Policy, Duke University, Durham, North Carolina, U.S.A.
    Search for more papers by this author
  • Nicole Soranzo,

    1. The Department of Biology, University College London, London, U.K.
    Search for more papers by this author
  • John Mulley,

    1. Department of Genetic Medicine, Women's and Children's Hospital, and School of Molecular and Biomedical Sciences, The University of Adelaide, South Australia, Australia
    Search for more papers by this author
  • Colin P. Doherty,

    1. The Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, and Division of Neurology, Beaumont Hospital, Dublin, Ireland
    Search for more papers by this author
  • Ashish Kapoor,

    1. Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
    Search for more papers by this author
  • Chantal Depondt,

    1. The Department of Molecular Neurosciences, the Institute of Neurology, University College London, Queen Square, London, U.K.
    Search for more papers by this author
  • John M. Lynch,

    1. The Department of Clinical and Experimental Epilepsy, the Institute of Neurology, University College London. & National Society for Epilepsy, Chalfont St. Peter, Bucks, U.K.
    Search for more papers by this author
  • Ingrid E. Scheffer,

    1. Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia
    2. Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Melbourne, Australia
    Search for more papers by this author
  • Armin Heils,

    1. Clinic of Epileptology and Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University of Bonn, Germany
    Search for more papers by this author
  • Anne Gehrmann,

    1. Gene Mapping Center, Max-Delbrück-Center for Molecular Medicine, and Department of Neurology, Charité University Medicine, Humboldt University of Berlin, Germany
    Search for more papers by this author
  • Peter Kinirons,

    1. The Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, and Division of Neurology, Beaumont Hospital, Dublin, Ireland
    Search for more papers by this author
  • Sonia Gandhi,

    1. The Department of Molecular Neurosciences, the Institute of Neurology, University College London, Queen Square, London, U.K.
    Search for more papers by this author
  • Parthasarathy Satishchandra,

    1. The Department of Neurology, National Institute of Mental Health and Neuro Sciences, Bangalore, India
    Search for more papers by this author
  • Nicholas W. Wood,

    1. The Department of Molecular Neurosciences, the Institute of Neurology, University College London, Queen Square, London, U.K.
    Search for more papers by this author
  • Anuranjan Anand,

    1. Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
    Search for more papers by this author
  • Thomas Sander,

    1. Gene Mapping Center, Max-Delbrück-Center for Molecular Medicine, and Department of Neurology, Charité University Medicine, Humboldt University of Berlin, Germany
    Search for more papers by this author
  • Samuel F. Berkovic,

    1. Department of Medicine, The University of Melbourne, Austin Health, Melbourne, Australia
    Search for more papers by this author
  • Norman Delanty,

    1. The Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, and Division of Neurology, Beaumont Hospital, Dublin, Ireland
    Search for more papers by this author
  • David B. Goldstein,

    1. The Institute for Genome Science and Policy, Duke University, Durham, North Carolina, U.S.A.
    Search for more papers by this author
  • Sanjay M. Sisodiya

    1. The Department of Clinical and Experimental Epilepsy, the Institute of Neurology, University College London. & National Society for Epilepsy, Chalfont St. Peter, Bucks, U.K.
    Search for more papers by this author

Address for correspondence and reprint requests to Dr. Sanjay M. Sisodiya at the Department of Clinical and Experimental Epilepsy, the Institute of Neurology, University College London, Queen Square, London WC1N 3BG, U.K., & National Society for Epilepsy, Chesham Lane, Chalfont St. Peter, Bucks, SL9 0RJ, U.K. E-mail: s.sisodiya@ion.ucl.ac.uk; or Dr. David Goldstein at the Institute for Genome Science and Policy, Duke University, 103 Research Dr, Durham, NC 27710 U.S.A. E-mail: d.goldstein@duke.edu

Abstract

Summary: Purpose: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls.

Methods: The strongest candidate causal variant from the original report (rs3918149) was genotyped across all five cohorts. In an effort to identify novel candidate causal polymorphisms, previously unscreened regions of UTR were resequenced.

Results: We observed a significant effect in a small sample recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a sample recruited in Ireland and no association in larger samples of German, Australian, and Indian populations. There was no association with other common forms of epilepsy or any other clear candidate casual variants in or near the BRD2 region.

Conclusions: The replication of an effect in the British cohort and suggestive evidence from that recruited in Ireland but lack of replication from the larger German, Australian, and Indian cohorts is surprising and difficult to explain. Further replication in carefully matched populations is required. Results presented here do not, however, support a strong effect for susceptibility to JME across populations of European descent.

Ancillary