Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in children and adolescents with obsessive-compulsive disorder.
Dysfunction of the central serotonergic system has been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). The genetic contribution to the development of OCD is particularly high in early-onset OCD. The aim of this study was to investigate the effect of polymorphic variants in the gene of the novel brain-specific tryptophan hydroxylase-2 (TPH2), the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain, in OCD with disease onset in childhood and adolescence. We analysed two common single nucleotide polymorphisms (SNPs) of TPH2 in the putative transcriptional control region and in intron 2 of the TPH2 gene in a unique family-based sample of OCD patients with onset of the disease in childhood and adolescence comprising 71 complete, independent trios. The transmission disequilibrium test was used to determine transmission of alleles and haplotypes from parents to offspring. In this first study of TPH2 in OCD, analysis of the SNPs, rs4570625 and rs4565946, revealed a significant preferential transmission of haplotype G-C to children and adolescents with OCD. Moreover, a trend towards preferential transmission of the C allele of SNP rs4565946 to the patients was found. The genotype relative-risk estimate for homozygous C allele carriers of SNP rs4565946 was 2.58 (95% CI 0.98-6.82). In conclusion, the results link TPH2 variations to the pathogenesis of early-onset OCD and further support the aetiological relevance of 5-HT signalling in OCD.
Mössner
Rainald
R
Clinical and Molecular Psychobiology, Department of Psychiatry and Psychotherapy, University of Würzburg, Füchsleinstrasse 15, 97080 Würzburg, Germany. rainald.moessner@mail.uni-wuerzburg.de
Walitza
Susanne
S
Geller
Frank
F
Scherag
André
A
Gutknecht
Lise
L
Jacob
Christian
C
Bogusch
Lisa
L
Remschmidt
Helmut
H
Simons
Michael
M
Herpertz-Dahlmann
Beate
B
Fleischhaker
Christian
C
Schulz
Eberhard
E
Warnke
Andreas
A
Hinney
Anke
A
Wewetzer
Christoph
C
Lesch
Klaus-Peter
KP
D000293:Adolescent; D002648:Child; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D015810:Linkage Disequilibrium / Q000235:genetics*; D008297:Male; D009771:Obsessive-Compulsive Disorder / Q000175:diagnosis / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D014365:Tryptophan Hydroxylase / Q000235:genetics*
C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase