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Background  Disturbances in serotonin neurotransmission are implicated in the etiology of many psychiatric disorders, including bipolar affective disorder (BPD). The tryptophan hydroxylase gene ( TPH ), which codes for the enzyme catalyzing the rate-limiting step in serotonin biosynthetic pathway, is one of the leading candidate genes for psychiatric and behavioral disorders. In a preliminary study, we found that  TPH1  intron7 A218C polymorphism was associated with BPD. This study was designed to investigate sequence variants of the  TPH1  gene in Taiwanese and to test whether the  TPH1  gene is a susceptibility factor for the BPD.    Methods  Using a systematic approach, we have searched the exons and promoter region of the  TPH1  gene for sequence variants in Taiwanese Han and have identified five variants, A-1067G, G-347T, T3804A, C27224T, and A27237G. These five variants plus another five taken from the literature and a public database were examined for an association in 108 BPD patients and 103 controls; no association was detected for any of the 10 variants.    Results  Haplotype constructions using these 10 SNPs showed that the 3 most common haplotypes in both patients and controls were identical. One of the fourth common haplotype in the patient group (i.e. GGGAGACCCA) was unique and showed a trend of significance with the disease (P = 0.028). However, the significance was abolished after Bonferroni correction thus suggesting the association is weak. In addition, three haplotype-tagged SNPs (htSNPs) were selected to represent all haplotypes with frequencies larger than 2% in the Taiwanese Han population. The defined  TPH1  htSNPs significantly reduce the marker number for haplotype analysis thus provides useful information for future association studies in our population.    Conclusion  Results of this study did not support the role of  TPH1  gene in BPD etiology. As the current studies found the  TPH1  gene under investigation belongs to the peripheral serotonin system and may link to a cardiac dysfunction phenotype, a second TPH gene that functions predominantly in the brain (i.e., nTPH or TPH2) should be the target for the future association study.

Polymorphism screening and haplotype analysis of the tryptophan hydroxylase gene (TPH1)and association with bipolar affective disorder in Taiwan