Human Molecular Genetics Advance Access published online on September 27, 2007
Human Molecular Genetics, 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 & Brain Center, University of Bonn, Bonn, Germany 2 Institute of Human Genetics, University of Bonn, Bonn, Germany 3 Department of Biomedicine, University of Bergen, Bergen, Norway 4 Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany 5 Central Institute for Mental Health, Division Genetic Epidemiology in Psychiatry, Mannheim, Germany 6 Department of Neurology, Laboratories of Neurogenetics, University of California, San Francisco, USA 7 Russian State Medical University, Moscow, Russia 8 Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerp, Belgium 9 Mental Health Research Center, Moscow, Russia 10 Moscow Research Institute of Psychiatry, Moscow, Russia 11 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway 12 Department of Psychiatry, University of Bonn, Bonn, Germany
Address for correspondence: Sven Cichon, PhD, Department of Genomics, Life & Brain Center, University of Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany. E-mail: sven.cichon{at}uni-bonn.de. Phone: +49 228 6885 405, FAX: +49 228 6885 401
Received June 25, 2007; Revised September 24, 2007; Accepted September 24, 2007
The neurotransmitter serotonin (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 etiology 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 bipolar affective disorder from Germany and Russia, totalling 883 patients and 1,300 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% C.I. 1.2 - 1.9) for rs11178997 (in the 5'-associated haplotype block) and 4.8 (95% C.I. 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-hydroxytryptamine (serotonin) production in the brain as a pathophysiological mechanism in bipolar affective disorder.