Polymorphisms in the 5 '-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression

Duan, J., Sanders, A. R., Vander Molen, J., Martinolich, L., Mowry, B. J., Levinson, D. F., Crowe, R. R., Silverman, J. M. and Gejman, P. V. (2003) Polymorphisms in the 5 '-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression. Molecular Psychiatry, 8 11: 901-910. doi:10.1038/sj.mp.4001403

Author Duan, J.
Sanders, A. R.
Vander Molen, J.
Martinolich, L.
Mowry, B. J.
Levinson, D. F.
Crowe, R. R.
Silverman, J. M.
Gejman, P. V.
Title Polymorphisms in the 5 '-untranslated region of the human serotonin receptor 1B (HTR1B) gene affect gene expression
Journal name Molecular Psychiatry   Check publisher's open access policy
ISSN 1359-4184
Publication date 2003
Sub-type Article (original research)
DOI 10.1038/sj.mp.4001403
Volume 8
Issue 11
Start page 901
End page 910
Total pages 10
Editor Julio Licinio
Place of publication United Kingdom
Publisher Nature Publishing Group
Collection year 2003
Language eng
Subject C1
321021 Psychiatry
730211 Mental health
Abstract We present evidence of complex balancing regulation of HTR1B transcription by common polymorphisms in its promoter. Computational analysis of the HTR1B gene predicted that a 50 segment, spanning common DNA sequence variations, T-261G, A-161T, and -182INS/DEL-181, contained a putative functional promoter. Using a secreted alkaline phosphatase (SEAP) reporter gene system, we found that the haplotype -261G_-182INS-181_A-161 enhanced transcriptional activity 2.3-fold compared with the haplotype T-261_-182INS-181_A-161. Conversely, -161T reversed this, and the net effect when -261G and -161T were in the same haplotype (-261G_-182INS-181_-161T) was equivalent to the major haplotype (T-261_-182INS-181_A-161). Electrophoretic mobility shift experiments showed that -261G and -161T modify the binding of transcription factors (TFs): -261G generates a new AP2 binding site, while alleles A-161 and -161T exhibit different binding characteristics to AP1. T-261G and A-161T were found to be in linkage disequilibrium (LD) with G861C in a European ancestry population. Interestingly, G861C has been reported to be associated with several psychiatric disorders. Our results indicate that HTR1B is the target of substantial transcriptional genetic regulation by common haplotypes, which are in LD with the HTR1B single-nucleotide polymorphism (SNP) most commonly used in association studies.
Keyword Biochemistry & Molecular Biology
Mental Disorders
Gene Expression
Single-nucleotide Polymorphisms
5-ht1b Receptor
Linkage Disequilibrium
Alcohol Dependence
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2004 Higher Education Research Data Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 57 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 15 Aug 2007, 02:21:06 EST