• Online Features  This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (41)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Topic Collections  • Psychiatry  • Bipolar Disorder  • Genetics  • Genetic Disorders  • Alert me on articles by topic  Social Bookmarking   What's this?

Yi-Mei J. Lin, PhD; Shin-Chih Chao, MD; Tsung-Ming Chen, MS; Te-Jen Lai, MD; Jia-Shing Chen, MS; H. Sunny Sun, PhD

Arch Gen Psychiatry. 2007;64(9):1015-1024.

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 < .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 single-nucleotide 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.

Author Affiliations: Institute of Basic Medical Sciences (Drs Lin and Sun and Messrs T.-M. Chen and J.-S. Chen) and Institute of Molecular Medicine (Drs Chao and Sun), National Cheng Kung University Medical College, Tainan, Taiwan; and Department of Psychiatry, Chung Shan Medical University Hospital, Taichung, Taiwan (Dr Lai).

CiteULike    Connotea    Delicious    Digg    Facebook    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Attention-Deficit/Hyperactivity Disorder Symptoms in Offspring of Mothers With Impaired Serotonin Production
Halmoy et al.
Arch Gen Psychiatry 2010;67:1033-1043.
ABSTRACT | FULL TEXT  

A Regulatory Domain in the N Terminus of Tryptophan Hydroxylase 2 Controls Enzyme Expression
Murphy et al.
J. Biol. Chem. 2008;283:13216-13224.
ABSTRACT | FULL TEXT  

Role of GSK3{beta} in behavioral abnormalities induced by serotonin deficiency
Beaulieu et al.
Proc. Natl. Acad. Sci. USA 2008;105:1333-1338.
ABSTRACT | FULL TEXT