1. Common and Rare Variant Analysis in Early-Onset Bipolar Disorder Vulnerability
- Author
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Liu, Chunyu, Cichon, Sven, Degenhardt, Franziska, Mattheisen, Manuel, Priebe, Lutz, Mathieu, Flavie, Kahn, Jean-Pierre, Henry, Chantal, Boland, Anne, Zelenika, Diana, Gut, Ivo, Heath, Simon, Etain, Bruno, Lathrop, Mark, Maier, Wolfgang, Albus, Margot, Rietschel, Marcella, Schulze, Thomas G., McMahon, Francis J., Kelsoe, John R., Hamshere, Marian, Craddock, Nicholas, Nöthen, Markus M., Mühleisen, Thomas, Bellivier, Frank, Leboyer, Marion, Georgi, Alexander, Zidane, Nora, Chevallier, Lucie, Deshommes, Jasmine, Nicolas, Aude, Henrion, Annabelle, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Fondation FondaMental [Créteil], Department of Genomics, Life and Brain Center, University of Bonn, Institute of Human Genetics, Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Division of Medical Genetics, University of Basel (Unibas), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Department of Psychiatry, Plate-forme de Resources Biologiques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Albert Chenevier, CIC - CHU Henri Mondor, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Service de Psychiatrie et Psychologie Clinique, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Hôpital Jeanne-d'Arc, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Department of Psychiatry and Psychotherapy, Georg-August-University [Göttingen], Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health [Bethesda] (NIH), University of California [San Diego] (UC San Diego), University of California-University of California, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]-Medical Research Council (MRC), Pôle de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Medical Research Council (MRC)-School of Medicine [Cardiff], Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University, Guellaen, Georges, Georg-August-University = Georg-August-Universität Göttingen, University of California (UC)-University of California (UC), Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], Universität Bonn = University of Bonn, and University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim
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Male ,Bipolar Disorder ,lcsh:Medicine ,Genome-wide association study ,Disease ,Bioinformatics ,Cohort Studies ,Chromosomal Disorders ,Medicine and Health Sciences ,Age of Onset ,lcsh:Science ,Genetics ,Multidisciplinary ,Genomics ,3. Good health ,Meta-analysis ,Medical genetics ,Female ,ddc:500 ,Research Article ,medicine.medical_specialty ,Biology ,Bipolar disorder ,Chromosomes ,Genomic databases ,Genotyping ,Human genetics ,Polymerase chain reaction ,Polymorphism, Single Nucleotide ,White People ,Young Adult ,Molecular genetics ,Mental Health and Psychiatry ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,medicine ,Genome-Wide Association Studies ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Genetic Predisposition to Disease ,Genetic Association Studies ,Clinical Genetics ,Mood Disorders ,lcsh:R ,Biology and Life Sciences ,Computational Biology ,Human Genetics ,medicine.disease ,Genome Analysis ,R1 ,Genetics of Disease ,RC0321 ,lcsh:Q ,Age of onset ,Genome-Wide Association Study - Abstract
The team of M. Leboyer is part of the École des Neurosciences de Paris Ile-de-France network, member of the Bio-Psy Labex and member of the European Network of Bipolar Research Expert Centres (ENBREC).; International audience; 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.
- Published
- 2014
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