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

Sven Cichon, Ingeborg Winge, Manuel Mattheisen, Alexander Georgi, Anna Karpushova, Jan Freudenberg, Yun Freudenberg-Hua, Gulia Babadjanova, Ann Van den Bogaert, Lilia I. Abramova, Sofia Kapiletti, Per M. Knappskog, Jeffrey Mckinney, Wolfgang Maier, Rami Abou Jamra, Thomas G. Schulze, Johannes Schumacher, Peter Propping, Marcella Rietschel, Jan HaavikMarkus M. Nöthen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)87-97
Number of pages11
JournalHuman Molecular Genetics
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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