title: 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 early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). 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 P-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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Jamain
authors.affiliation: Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany; Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France; Assistance Publique - Hôpitaux de Paris, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatry, Créteil, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Etain
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Mühleisen
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany; Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Georgi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France.
authors.forename: Nora
authors.initials: N
authors.lastname: Zidane
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Chevallier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France; Assistance Publique - Hôpitaux de Paris, Hôpital Henri Mondor-Albert Chenevier, Plate-forme de Resources Biologiques, Créteil, France; 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.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Deshommes
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Henrion
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Degenhardt
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany; Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Priebe
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France.
authors.forename: Flavie
authors.initials: F
authors.lastname: Mathieu
authors.affiliation: Fondation FondaMental, Créteil, France; Département de Psychiatrie et de Psychologie Clinique, Centre Hospitalier Universitaire de Nancy, Hôpital Jeanne-d'Arc, Toul, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kahn
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France; Assistance Publique - Hôpitaux de Paris, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatry, Créteil, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Henry
authors.affiliation: Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Boland
authors.affiliation: Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.affiliation: Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.affiliation: Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.affiliation: Commissariat à l'Energie Atomique, Institut Génomique, Centre National de Génotypage, Evry, France.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maier
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany.
authors.forename: Margot
authors.initials: M
authors.lastname: Albus
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany; Department of Psychiatry, University of Bonn, Bonn, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany; Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-Universität, Göttingen, Germany.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
authors.affiliation: 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.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: McMahon
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, CA, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Kelsoe
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
authors.forename: Marian
authors.initials: M
authors.lastname: Hamshere
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Heath Park, Cardiff, United Kingdom.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Craddock
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Fondation FondaMental, Créteil, France; Assistance Publique - Hôpitaux de Paris, Groupe Hospitalier Lariboisière-F. Widal, Pôle de Psychiatrie, Paris, France; Université Paris Diderot, Paris, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Bellivier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U955, Psychiatrie Génétique, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France; Fondation FondaMental, Créteil, France; Assistance Publique - Hôpitaux de Paris, Hôpital Henri Mondor-Albert Chenevier, Pôle de Psychiatry, Créteil, France.
authors.forename: Marion
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authors.lastname: Leboyer
mesh_terms: D017668:Age of Onset; D001714:Bipolar Disorder / Q000453:epidemiology* / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D055815:Young Adult
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