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European collaborative study of early-onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset.

Flavie Mathieu 1, 2, * Marie-Hélène Dizier 3, 4, 5 Bruno Etain 1, 2, 6 Stéphane Jamain 1, 2 Marcella Rietschel 7 Wolfgang Maier 8 Margot Albus 9 Patrick Mckeon 10 Siobhan Roche 11 Douglas Blackwood 12 Walter J. Muir 12 Chantal Henry 1, 2, 6 Alain Malafosse 13 Martin Preisig 14 François Ferrero 15 Sven Cichon 16 Johannes Schumacher 17 Stephanie Ohlraun 8 Peter Propping 17 Rami Abou Jamra 17 Thomas G. Schulze 7, 18 Diana Zelenica 19 Céline Charon 19 Andrej Marusic 20 Mojca Z. Dernovsek 20 Hugh Gurling 21 Markus M. Nöthen 17 Mark Lathrop 19 Marion Leboyer 1, 2, 6 Frank Bellivier 1, 2, 6 
Abstract : Bipolar disorder has a genetic component, but the mode of inheritance remains unclear. A previous genome scan conducted in 70 European families led to detect eight regions linked to bipolar disease. Here, we present an investigation of whether the phenotypic heterogeneity of the disorder corresponds to genetic heterogeneity in these regions using additional markers and an extended sample of families. The MLS statistic was used for linkage analyses. The predivided sample test and the maximum likelihood binomial methods were used to test genetic homogeneity between early-onset bipolar type I (cut-off of 22 years) and other types of the disorder (later onset of bipolar type I and early-onset bipolar type II), using a total of 138 independent bipolar-affected sib-pairs. Analysis of the extended sample of families supports linkage in four regions (2q14, 3p14, 16p23, and 20p12) of the eight regions of linkage suggested by our previous genome scan. Heterogeneity testing revealed genetic heterogeneity between early and late-onset bipolar type I in the 2q14 region (P = 0.0001). Only the early form of the bipolar disorder but not the late form appeared to be linked to this region. This region may therefore include a genetic factor either specifically involved in the early-onset bipolar type I or only influencing the age at onset (AAO). Our findings illustrate that stratification according to AAO may be valuable for the identification of genetic vulnerability polymorphisms. © 2010 Wiley-Liss, Inc.
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Flavie Mathieu, Marie-Hélène Dizier, Bruno Etain, Stéphane Jamain, Marcella Rietschel, et al.. European collaborative study of early-onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset.. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, Wiley, 2010, 153B (8), pp.1425-33. ⟨10.1002/ajmg.b.31121⟩. ⟨inserm-00559668⟩

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