The International Journal of Neuropsychopharmacology

Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation

Lise Gutknecht a1 1 , Christian Jacob a1 1 , Alexander Strobel a2 1 , Claudia Kriegebaum a1, Johannes Müller a2, Yong Zeng a1, Christoph Markert a1, Andrea Escher a1, Jens Wendland a1, Andreas Reif a1, Rainald Mössner a1, Cornelius Gross a3, Burkhard Brocke a2 and Klaus-Peter Lesch a1c1
a1 Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, University of Würzburg, Würzburg, Germany
a2 Differential and Personality Psychology, Institute of Psychology II, Dresden University of Technology, Dresden, Germany
a3 Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy

Article author query
gutknecht l   [PubMed][Google Scholar] 
jacob c   [PubMed][Google Scholar] 
strobel a   [PubMed][Google Scholar] 
kriegebaum c   [PubMed][Google Scholar] 
muller j   [PubMed][Google Scholar] 
zeng y   [PubMed][Google Scholar] 
markert c   [PubMed][Google Scholar] 
escher a   [PubMed][Google Scholar] 
wendland j   [PubMed][Google Scholar] 
reif a   [PubMed][Google Scholar] 
mossner r   [PubMed][Google Scholar] 
gross c   [PubMed][Google Scholar] 
brocke b   [PubMed][Google Scholar] 
lesch kp   [PubMed][Google Scholar] 


Variation in the tryptophan hydroxylase-2 gene (TPH2) coding for the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain modulates responses of limbic circuits to emotional stimuli and has been linked to a spectrum of clinical populations characterized by emotional dysregulation. Here, we tested a set of common single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of TPH2 for association with personality traits and with risk for personality disorders in two cohorts comprising of 336 healthy individuals and 420 patients with personality disorders. Personality dimensions were assessed by the Tridimensional Personality Questionnaire (TPQ) and the revised NEO Personality Inventory (NEO-PI-R). Personality disorders were diagnosed with the Structured Clinical Interview of DSM-IV and were allocated to clusters A, B, and C. Individual SNP and haplotype analyses revealed significant differences in genotype frequencies between controls and cluster B as well as cluster C patients, respectively. In both patient groups, we observed overrepresentation of T allele carriers of a functional polymorphism in the upstream regulatory region of TPH2 (SNP G-703T, rs4570625) which was previously shown to bias responsiveness of the amygdala, a structure critically involved in emotionality. Furthermore, significant effects of TPH2 variants on anxiety-related traits defined primarily by the TPQ Harm Avoidance were found in healthy individuals. The results link potentially functional TPH2 variants to personality traits related to emotional instability as well as to cluster B and cluster C personality disorders. These findings implicate alterations of 5-HT synthesis in emotion regulation and confirm TPH2 as a susceptibility and/or modifier gene of affective spectrum disorders.

(Received February 27 2006)
(Reviewed April 3 2006)
(Revised October 9 2006)
(Accepted October 24 2006)
(Published Online December 19 2006)

Key Words: Anxiety; emotion regulation; gene variation; personality disorders; personality traits; serotonin; tryptophan hydroxylase 2.

c1 Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, University of Würzburg, Füchsleinstr. 15, 97080 Würzburg, Germany. Tel.: +49-931-201 77600 Fax: +49-931-201 77620 E-mail:


1 These authors contributed equally to the work.