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

Stéphane Jamain, Sven Cichon, Bruno Etain, Thomas W. Mühleisen, Alexander Georgi, Nora Zidane, Lucie Chevallier, Jasmine Deshommes, Aude Nicolas, Annabelle Henrion, Franziska Degenhardt, Manuel Mattheisen, Lutz Priebe, Flavie Mathieu, Jean Pierre Kahn, Chantal Henry, Anne Boland, Diana Zelenika, Ivo Gut, Simon HeathMark Lathrop, Wolfgang Maier, Margot Albus, Marcella Rietschel, Thomas G. Schulze, Francis J. McMahon, John R. Kelsoe, Marian Hamshere, Nicholas Craddock, Markus M. Nöthen, Frank Bellivier, Marion Leboyer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere104326
JournalPloS one
Volume9
Issue number8
DOIs
StatePublished - Aug 11 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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