Brain-specific tryptophan hydroxylase 2 (TPH2):: a functional Pro206Ser substitution and variation in the 5′-region are associated with bipolar affective disorder

被引:93
作者
Cichon, Sven [1 ,2 ]
Winge, Ingeborg [5 ]
Mattheisen, Manuel [1 ,3 ]
Georgi, Alexander [6 ]
Karpushova, Anna [1 ]
Freudenberg, Jan [7 ]
Freudenberg-Hua, Yun [2 ]
Babadjanova, Gulia [8 ]
Van Den Bogaert, Ann [9 ]
Abramova, Lilia I. [10 ]
Kapiletti, Sofia [11 ]
Knappskog, Per M. [12 ]
McKinney, Jeffrey [5 ]
Maier, Wolfgang [4 ]
Abou Jamra, Rami [2 ]
Schulze, Thomas G. [6 ]
Schumacher, Johannes [2 ]
Propping, Peter [2 ]
Rietschel, Marcella [6 ]
Haavik, Jan [5 ]
Noethen, Markus M. [1 ,2 ]
机构
[1] Univ Bonn, Dept Genom, Life & Brain Ctr, D-53127 Bonn, Germany
[2] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany
[3] Univ Bonn, Inst Med Biometry Informat & Epidemiol, D-5300 Bonn, Germany
[4] Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany
[5] Univ Bergen, Dept Biomed, Bergen, Norway
[6] Cent Inst Mental Hlth, Div Genet Epidemiol Psychiat, D-6800 Mannheim, Germany
[7] Univ Calif San Francisco, Dept Neurol, Labs Neurogenet, San Francisco, CA 94143 USA
[8] Russian State Med Univ, Moscow 117437, Russia
[9] Univ Antwerp VIB, Dept Mol Genet, B-2610 Antwerp, Belgium
[10] Russian Acad Med Sci, Mental Hlth Res Ctr, Moscow 109801, Russia
[11] Moscow Res Inst Psychiat, Moscow, Russia
[12] Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway
关键词
D O I
10.1093/hmg/ddm286
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:87 / 97
页数:11
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