Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder.
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.
Cichon
Sven
S
Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. sven.cichon@uni-bonn.de
Winge
Ingeborg
I
Mattheisen
Manuel
M
Georgi
Alexander
A
Karpushova
Anna
A
Freudenberg
Jan
J
Freudenberg-Hua
Yun
Y
Babadjanova
Gulia
G
Van Den Bogaert
Ann
A
Abramova
Lilia I
LI
Kapiletti
Sofia
S
Knappskog
Per M
PM
McKinney
Jeffrey
J
Maier
Wolfgang
W
Jamra
Rami Abou
RA
Schulze
Thomas G
TG
Schumacher
Johannes
J
Propping
Peter
P
Rietschel
Marcella
M
Haavik
Jan
J
Nöthen
Markus M
MM
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
D017931:DNA Primers; D011994:Recombinant Proteins; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase