Tryptophan hydroxylase-1 gene variants associated with schizophrenia.
BACKGROUND
Serotonin (5-HT) has been implicated in the pathophysiology of schizophrenia. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), and as such it might be related to the pathogenesis of schizophrenia. Two isoforms are known, TPH-1 and TPH-2. TPH-1 association with schizophrenia is debated.


METHODS
A case-control design was employed for gene-disease association in 155 schizophrenic psychosis patients and 253 healthy controls, all North European Caucasians. Six single nucleotide polymorphisms (SNPs) with a haplotype block structure spanning over 23 kb of the total TPH-1 29 kb were analyzed. Linkage disequilibrium and haplotype analyses were performed. Bonferroni correction was used for multiple testing.


RESULTS
Single marker association analyses showed two SNPs significantly associated with schizophrenia. Several haplotypes were associated with the disease. A "sliding window" analysis attributed the strongest disease association to a haplotype configuration localized between the promoter region and intron 3.


CONCLUSIONS
Our data indicate that TPH-1 associates with schizophrenia. It appears that specific combinations of promoter variants vis-à-vis gene transcript variants contribute to genetic predisposition to the disease.
Zaboli
Ghazal
G
Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institute and Hospital, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden. ghazal.zaboli@ki.se
Jönsson
Erik G
EG
Gizatullin
Rinat
R
Asberg
Marie
M
Leopardi
Rosario
R
D000328:Adult; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000235:genetics*; D014365:Tryptophan Hydroxylase / Q000235:genetics*
D014365:Tryptophan Hydroxylase