Context:The tryptophan hydroxylase 2 (TPH2) gene encodes the first (also the rate-limiting) enzyme in the serotonin biosynthetic pathway. Despite reports of possible associations between polymorphisms in human TPH2 and many psychiatric disorders, including bipolar disorder (BPD), the functional effect and susceptibility loci of such polymorphisms for BPD have not yet been identified. Objectives:To examine the association of TPH2 with BPD and to identify the functional variants that may be involved in the pathophysiological development of BPD.Design, Setting, and Patients: We systematically screened all exons and promoters of the TPH2 gene in Han Chinese subjects to identify sequence variants. Association tests were conducted in 105 cases and 106 control subjects using single-locus, linkage disequilibrium, and haplotype analyses. Two promoter and one exon 2 single-nucleotide polymorphisms were examined for their functional role using a reporter gene system and enzyme activity assay, respectively. Additional statistical analysis was performed to study the interaction between the 2 TPH genes in 205 study participants with TPH1 and TPH2 genotype data.Results: Significant haplotype association of TPH2 polymorphisms and BPD was identified (P Ͻ.001). In addition, allelic alteration of polymorphisms in the promoter region and exon 2 of TPH2 caused noteworthy functional losses in promoter and enzyme activities, respectively, indicating the potential susceptibility loci for BPD. We found that the odds ratio changed from 3.73 of the TAG haplotype to 4.81 or 1.68, depending on the combined effect of both TPH genotypes. These data suggested an interaction between the 2 TPH genes to confer a risk for BPD.Conclusions: This study supports the involvement of TPH2 in the etiology of BPD, and the functional singlenucleotide polymorphisms identified herein might be the susceptibility loci for BPD. Although the interaction between the 2 TPH genes merits further investigation, our findings suggest that the interactive effect should be considered in future studies of serotonin-related disorders.