title: Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation.
abstract: 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.
authors.affiliation: Molecular and Clinical Psychobiology, Department for Psychiatry and Psychotherapy, University of Würzburg, Füchsleinstrasse 15, 97080 Würzburg,Germany.
authors.forename: Lise
authors.initials: L
authors.lastname: Gutknecht
authors.forename: Christian
authors.initials: C
authors.lastname: Jacob
authors.forename: Alexander
authors.initials: A
authors.lastname: Strobel
authors.forename: Claudia
authors.initials: C
authors.lastname: Kriegebaum
authors.forename: Johannes
authors.initials: J
authors.lastname: Müller
authors.forename: Yong
authors.initials: Y
authors.lastname: Zeng
authors.forename: Christoph
authors.initials: C
authors.lastname: Markert
authors.forename: Andrea
authors.initials: A
authors.lastname: Escher
authors.forename: Jens
authors.initials: J
authors.lastname: Wendland
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.forename: Rainald
authors.initials: R
authors.lastname: Mössner
authors.forename: Cornelius
authors.initials: C
authors.lastname: Gross
authors.forename: Burkhard
authors.initials: B
authors.lastname: Brocke
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
mesh_terms: D000293:Adolescent; D000328:Adult; D000342:Affective Symptoms / Q000235:genetics* / Q000523:psychology; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001923:Brain Chemistry / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010551:Personality / Q000235:genetics*; D010554:Personality Disorders / Q000235:genetics / Q000523:psychology; D010556:Personality Tests; D011569:Psychiatric Status Rating Scales; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000502:physiology; D014364:Tryptophan / Q000172:deficiency; D014365:Tryptophan Hydroxylase / Q000235:genetics*
chemical_list: D012701:Serotonin; D014364:Tryptophan; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase