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Common and rare variant analysis in early-onset bipolar disorder vulnerability.

Stéphane Jamain 1, 2, * Sven Cichon 3, 4, 5, 6 Bruno Etain 1, 2, 7 Thomas Mühleisen 3, 4 Alexander Georgi 8, 9 Nora Zidane 1, 2 Lucie Chevallier 1, 2 Jasmine Deshommes 1, 2, 10, 11 Aude Nicolas 1, 2 Annabelle Henrion 1, 2 Franziska Degenhardt 3, 4 Manuel Mattheisen 3, 4, 12 Lutz Priebe 3, 4 Flavie Mathieu 1, 2 Jean-Pierre Kahn 2, 13 Chantal Henry 1, 2, 7 Anne Boland 14 Diana Zelenika 14 Ivo Gut 15 Simon Heath 14 Mark Lathrop 14 Wolfgang Maier 9 Margot Albus 8 Marcella Rietschel 8, 9 Thomas Schulze 8, 16 Francis Mcmahon 17 John Kelsoe 18 Marian Hamshere 19 Nicholas Craddock 19 Markus Nöthen 3, 4 Frank Bellivier 1, 2, 20 Marion Leboyer 1, 2, 7
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.
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Submitted on : Friday, September 26, 2014 - 1:41:27 PM
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Stéphane Jamain, Sven Cichon, Bruno Etain, Thomas Mühleisen, Alexander Georgi, et al.. Common and rare variant analysis in early-onset bipolar disorder vulnerability.. PLoS ONE, Public Library of Science, 2014, 9 (8), pp.e104326. ⟨10.1371/journal.pone.0104326⟩. ⟨inserm-01068813⟩



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