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Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14

Abstract

Preliminary studies suggested that age at onset (AAO) may help to define homogeneous bipolar affective disorder (BPAD) subtypes. This candidate symptom approach might be useful to identify vulnerability genes. Thus, the probability of detecting major disease-causing genes might be increased by focusing on families with early-onset BPAD type I probands. This study was conducted as part of the European Collaborative Study of Early Onset BPAD (France, Germany, Ireland, Scotland, Switzerland, England, Slovenia). We performed a genome-wide search with 384 microsatellite markers using non-parametric linkage analysis in 87 sib-pairs ascertained through an early-onset BPAD type I proband (AAO of 21 years or below). Non-parametric multipoint analysis suggested eight regions of linkage with P-values<0.01 (2p21, 2q14.3, 3p14, 5q33, 7q36, 10q23, 16q23 and 20p12). The 3p14 region showed the most significant linkage (genome-wide P-value estimated over 10 000 simulated replicates of 0.015 [0.01–0.02]). After genome-wide search analysis, we performed additional linkage analyses with increased marker density using markers in four regions suggestive for linkage and having an information contents lower than 75% (3p14, 10q23, 16q23 and 20p12). For these regions, the information content improved by about 10%. In chromosome 3, the non-parametric linkage score increased from 3.51 to 3.83. This study is the first to use early-onset bipolar type I probands in an attempt to increase sample homogeneity. These preliminary findings require confirmation in independent panels of families.

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Acknowledgements

The French study was supported by grants from Assistance Publique-Hôpitaux de Paris, Ministère de la Recherche (PHRC, AOM98152) and the National Alliance for Research on Schizophrenia and Depression (NARSAD). B Etain received a grant from Institut National de la Santé et de la Recherche Médicale (Poste d’Accueil INSERM). The German study received the following support: the National Genomic Network (NGFN) of the German Ministry of Education and Research, the Deutsche Forschungsgemeinschaft (SFB 400 subprojects D1 and D3, Graduiertenkolleg GRK 246, FOR 423 subproject D1), the Alfried Krupp von Bohlen und Halbach-Stiftung, the Interuniversity Attraction Poles program P5/19 of the Belgian Federal Science Policy Office, and the National Alliance for Research on Schizophrenia and Depression (NARSAD). Research at the District Hospital Haar was supported by grants from the German Research Society (DFG), AL 230-1/2/3–230-5/1/2 and the SFB 400. D Blackwood and W Muir were supported by grants from The Health Foundation, London. The Medical Research Council, UK; The Chief Scientist Office of the Scottish Executive. The Irish study was supported by Aware, the Irish charity helping to defeat depression, the Health Research Board (H01069 HRB RP153/2000), and the Friends of St Patrick's Hospital. The Swiss study was supported by five grants from the Swiss National Foundation (#32-40677.94 to F Ferrero, #32-47315.96 and # 32-061974.00 to M Preisig, #32-66793.01 and #32-102168.03 to A Malafosse). We thank all the families who participated to this study. We thank Magalie Duroux (Laboratory INSERM U513 – Créteil, France) for preparing DNA samples for genotyping. We thank Catherine Bonaïti-Pellié for helpful comments about this work.

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Etain, B., Mathieu, F., Rietschel, M. et al. Genome-wide scan for genes involved in bipolar affective disorder in 70 European families ascertained through a bipolar type I early-onset proband: supportive evidence for linkage at 3p14. Mol Psychiatry 11, 685–694 (2006). https://doi.org/10.1038/sj.mp.4001815

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