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Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons

Molecular Psychiatry volume 12, pages 491–501 (2007)Cite this article

Abstract

Tryptophan hydroxylase isoform 2 (TPH2) is expressed in serotonergic neurons in the raphe nuclei, where it catalyzes the rate-limiting step in the synthesis of the neurotransmitter serotonin. In search for functional polymorphisms within the TPH2 gene locus, we measured allele-specific expression of TPH2 mRNA in sections of human pons containing the dorsal and median raphe nuclei. Differences in allelic mRNA expression – referred to as allelic expression imbalance (AEI) – are a measure of cis-acting regulation of gene expression and mRNA processing. Two marker SNPs, located in exons 7 and 9 of TPH2 (rs7305115 and rs4290270, respectively), served for quantitative allelic mRNA measurements in pons RNA samples from 27 individuals heterozygous for one or both SNPs. Significant AEI (ranging from 1.2- to 2.5-fold) was detected in 19 out of the 27 samples, implying the presence of cis-acting polymorphisms that differentially affect TPH2 mRNA levels in pons. For individuals heterozygous for both marker SNPs, the results correlated well (r=0.93), validating the AEI analysis. AEI is tightly associated with the exon 7 marker SNP, in 17 of 18 subjects. Remarkably, expression from the minor allele exceeded that of the major allele in each case, possibly representing a gain-of-function. Genotyping of 20 additional TPH2 SNPs identified a haplotype block of five tightly linked SNPs for which heterozygosity is highly correlated with AEI and overall expression of TPH2 mRNA. These results reveal the presence of a functional cis-acting polymorphism, with high frequency in normal human subjects, resulting in increased TPH2 expression levels. The SNPs that correlate with AEI are closely linked to TPH2 SNPs previously shown to associate with major depression and suicide.

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Acknowledgements

This project was supported by NIDA 1R21 DA108744 (to WS), the Department of Pharmacology and a grant from the Psychiatric Research Foundation, Columbus Ohio (to DS). We thank Greg Young, Center for Biostatistics, Ohio State University for statistical analyses, Audrey Papp for advice on genotyping and AEI measurements, Andrew Johnson for help with computer program-related issues, and Gloria Smith for technical assistance with many of the assays.

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Authors and Affiliations

  1. Department of Pharmacology, The Ohio State University, Columbus, OH, USA

    J-E Lim, J Pinsonneault, W Sadee & D Saffen

  2. Neuroscience Graduate Studies Program, College of Medicine and Public Health, The Ohio State University, Columbus, OH, USA

    J-E Lim, W Sadee & D Saffen

  3. The OSU Program in Pharmacogenomics, The Ohio State University, Columbus, OH, USA

    J Pinsonneault, W Sadee & D Saffen

  4. Department of Psychiatry, The Ohio State University, Columbus, OH, USA

    W Sadee & D Saffen

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  1. J-E Lim
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Correspondence to W Sadee or D Saffen.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Lim, JE., Pinsonneault, J., Sadee, W. et al. Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons. Mol Psychiatry 12, 491–501 (2007). https://doi.org/10.1038/sj.mp.4001923

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