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

Jamain, Stéphane, Cichon, Sven, Etain, Bruno, Mühleisen, Thomas W., Georgi, Alexander, Zidane, Nora, Chevallier, Lucie, Deshommes, Jasmine, Nicolas, Aude, Henrion, Annabelle, Degenhardt, Franziska, Mattheisen, Manuel, Priebe, Lutz, Mathieu, Flavie, Kahn, Jean-Pierre, Henry, Chantal, Boland, Anne, Zelenika, Diana, Gut, Ivo, Heath, Simon, Lathrop, Mark, Maier, Wolfgang, Albus, Margot, Rietschel, Marcella, Schulze, Thomas G., McMahon, Francis J., Kelsoe, John R., Hamshere, Marian ORCID: https://orcid.org/0000-0002-8990-0958, Craddock, Nicholas ORCID: https://orcid.org/0000-0003-2171-0610, Nöthen, Markus M., Bellivier, Frank and Leboyer, Marion 2014. Common and rare variant analysis in early-onset bipolar disorder vulnerability. PLoS ONE 9 (8) , e104326. 10.1371/journal.pone.0104326

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher:	Public Library of Science
ISSN:	1932-6203
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	11 July 2014
Last Modified:	04 May 2023 10:05
URI:	https://orca.cardiff.ac.uk/id/eprint/74861

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