title: Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder.
abstract: 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.
authors: Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. sven.cichon@uni-bonn.de
authors: Sven
authors: S
authors: Cichon
authors: Ingeborg
authors: I
authors: Winge
authors: Manuel
authors: M
authors: Mattheisen
authors: Alexander
authors: A
authors: Georgi
authors: Anna
authors: A
authors: Karpushova
authors: Jan
authors: J
authors: Freudenberg
authors: Yun
authors: Y
authors: Freudenberg-Hua
authors: Gulia
authors: G
authors: Babadjanova
authors: Ann
authors: A
authors: Van Den Bogaert
authors: Lilia I
authors: LI
authors: Abramova
authors: Sofia
authors: S
authors: Kapiletti
authors: Per M
authors: PM
authors: Knappskog
authors: Jeffrey
authors: J
authors: McKinney
authors: Wolfgang
authors: W
authors: Maier
authors: Rami Abou
authors: RA
authors: Jamra
authors: Thomas G
authors: TG
authors: Schulze
authors: Johannes
authors: J
authors: Schumacher
authors: Peter
authors: P
authors: Propping
authors: Marcella
authors: M
authors: Rietschel
authors: Jan
authors: J
authors: Haavik
authors: Markus M
authors: MM
authors: Nöthen
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001714:Bipolar Disorder / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D001921:Brain / Q000201:enzymology*; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D004795:Enzyme Stability; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D011994:Recombinant Proteins; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase