Early-Onset Bipolar Disorder Vulnerability

Common and Rare Variant Analysis in Early-Onset Bipolar Disorder Vulnerability

Abstract

Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic Background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with earlyonset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes Encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal -values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and Need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.

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Forschungsgruppe: Stéphane Jamain (1,2,3), Sven Cichon (4,5,6,7), Bruno Etain (1,2,3,8), Thomas W. Mühleisen (5,6),  Alexander Georgi (9,10), Nora Zidane (1,2,3), Lucie Chevallier (1,2,3), Jasmine Deshommes (1,2,3,11,12),  Aude Nicolas (1,2,3), Annabelle Henrion (1,2,3), Franziska Degenhardt (5,6), Manuel Mattheisen (5,6,13),  Lutz Priebe (5,6), Flavie Mathieu (1,2,3), Jean-Pierre Kahn (3,14), Chantal Henry (1,2,3,8), Anne Boland (15), Diana Zelenika (15), Ivo Gut (15), Simon Heath (15), Mark Lathrop (15), Wolfgang Maier (10), Margot Albus (9), Marcella Rietschel (9,10), Thomas G. Schulze9 (16), Francis J. McMahon (17), John R. Kelsoe (18), Marian Hamshere (19), Nicholas Craddock (19), Markus M. Nöthen (5,6), Frank Bellivier (1,3,20,21), Marion Leboyer (1,2,3,8).

  1. Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France
  2. Université Paris-Est, Faculté de Médecine, Créteil, France,
  3. Fondation FondaMental, Créteil, France,
  4. Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany,
  5. Institute of Human Genetics, University of Bonn, Bonn, Germany,
  6. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany,
  7. Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland,
  8. Assistance Publique – Hôpitaux de Paris, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatry, Créteil, France,
  9. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany,
  10. Department of Psychiatry, University of Bonn, Bonn, Germany,
  11. Assistance Publique – Hôpitaux de Paris, Hôpital Henri Mondor-Albert Chenevier, Plate-forme de Resources Biologiques, Créteil, France,
  12. Institut National de la Santé et de la Recherche Médicale Centre d’Investigation Clinique 006, Hôpital Henri Mondor-Albert Chenevier, Pôle Recherche Clinique Santé Publique, Créteil, France,
  13. Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark,
  14. Département de Psychiatrie et de Psychologie Clinique, Centre Hospitalier Universitaire de Nancy, Hôpital Jeanne-d’Arc, Toul, France,
  15. Commissariat à l’Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France,
  16. Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-Universität, Göttingen, Germany,
  17. Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, United States of America,
  18. Department of Psychiatry, University of California San Diego, La Jolla, CA, United States of America,
  19. MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom,
  20. Assistance Publique – Hôpitaux de Paris, Groupe Hospitalier Lariboisière-F. Widal, Pôle de Psychiatrie, Paris, France,
  21. Université Paris Diderot, Paris, France

Citation: Jamain S, Cichon S, Etain B, Mühleisen TW, Georgi A, et al. (2014) Common and Rare Variant Analysis in Early-Onset Bipolar Disorder Vulnerability. Published August 11, 2014

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