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

Stéphane Jamain; Sven Cichon; Bruno Etain; Thomas 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 Heath; Mark Lathrop; Wolfgang Maier; Margot Albus; Marcella Rietschel; Thomas Schulze; Francis Mcmahon; John Kelsoe; Marian Hamshere; Nicholas Craddock; Markus Nöthen; Frank Bellivier; Marion Leboyer

doi:10.1371/journal.pone.0104326

Journal articles

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}

* Corresponding author

1 IMRB - Institut Mondor de Recherche Biomédicale

2 Fondation FondaMental [Créteil]

3 Department of Genomics, Life and Brain Center

4 Institute of Human Genetics

5 INM-1 - Institute of Neuroscience and Medicine

6 Division of Medical Genetics

7 Service de psychiatrie

8 Department of Genetic Epidemiology in Psychiatry

9 Department of Psychiatry

10 Plate-forme de Resources Biologiques

11 CIC - CHU Henri Mondor

12 Department of Biomedicine and the Centre for Integrative Sequencing

13 Service de Psychiatrie et Psychologie Clinique

14 CNG - Centre National de Génotypage

15 CNAG - Centro Nacional de Análisi Genómico

16 Department of Psychiatry and Psychotherapy

17 Unit on the Genetic Basis of Mood and Anxiety Disorders

18 Department of Psychiatry

19 MRC Centre for Neuropsychiatric Genetics and Genomics

20 Pôle de psychiatrie

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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Journal articles

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Life Sciences [q-bio] / Biochemistry, Molecular Biology

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