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A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia
Published on: June 15, 2011
Tryptophan hydroxylase-1 gene variants associated with schizophrenia
Ghazal Zaboli1, Erik G Jönsson, Rinat Gizatullin
1Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institute and Hospital, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden. ghazal.zaboli@ki.se
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.
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