Human Molecular Genetics Advance Access originally published online on September 27, 2007
Human Molecular Genetics 2008 17(1):87-97; doi:10.1093/hmg/ddm286
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Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder
1 Department of Genomics, Life and Brain Center 2 Institute of Human Genetics 3 Institute for Medical Biometry, Informatics and Epidemiology and 4 Department of Psychiatry, University of Bonn, Bonn, Germany 5 Department of Biomedicine, University of Bergen, Bergen, Norway 6 Central Institute for Mental Health, Division Genetic Epidemiology in Psychiatry, Mannheim, Germany 7 Department of Neurology, Laboratories of Neurogenetics, University of California, San Francisco, USA 8 Russian State Medical University, Moscow, Russia 9 Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium 10 Mental Health Research Center, Moscow, Russia 11 Moscow Research Institute of Psychiatry, Moscow, Russia 12 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
* To whom correspondence should be addressed at: Department of Genomics Life and Brain Center University of Bonn Sigmund-Freud Street 25, D-53127 Bonn, Germany. Tel: +49 2286885405; Fax: +49 2286885401; Email: sven.cichon{at}uni-bonn.de
Received June 25, 2007; Accepted September 24, 2007
The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] controls a broad range of biological functions that are disturbed in affective disorder. In the brain, 5-HT production is controlled by tryptophan hydroxylase 2 (TPH2). In order to assess the possible contribution of TPH2 genetic variability to the aetiology of bipolar affective disorder (BPAD), we systematically investigated common and rare genetic variation in the TPH2 gene through a sequential sequencing and SNP-based genotyping approach. Our study sample comprised two cohorts of BPAD from Germany and Russia, totalling 883 patients and 1300 controls. SNPs located in a haplotype block covering the 5' region of the gene as well as a rare, non-synonymous SNP, resulting in a Pro206Ser substitution, showed significant association with bipolar disorder. The odds ratio for the minor allele in the pooled sample was 1.5 (95% CI 1.2–1.9) for rs11178997 (in the 5'-associated haplotype block) and 4.8 (95% CI 1.6–14.8) for rs17110563 encoding the Pro206Ser substitution. Examination of the functional effects of TPH2 Pro206Ser provided evidence for a reduced thermal stability and solubility of the mutated enzyme, suggesting reduced 5-HT production in the brain as a pathophysiological mechanism in BPAD.