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Support for the involvement of TPH2 gene in affective disorders

Molecular Psychiatry volume 9, pages 980–981 (2004)Cite this article

SIR—Disturbance of the serotonergic system has been suggested as a factor in the pathogenesis of affective disorders. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the serotonin biosynthetic pathway and plays an important role in the regulation of serotonin function. Until recently, only one TPH isoform was reported for vertebrates. By targeted ablation of this TPH gene in mice, Walther et al1 discovered a new brain-specific TPH isoform, called TPH2. The gene encoding this isoform is located on the long arm of chromosome 12 that has been reported as a probable region for bipolar and major depressive disorder (MDD) susceptibility genes.2, 3, 4, 5 In a recent issue of Molecular Psychiatry, Zill et al6 reported SNP and haplotype association studies between the TPH2 gene and MDD. They used a case/control sample of 300 MDD individuals and 265 healthy diagnosed controls, and genotyped 10 SNPs covering approximately 28 kb between exons 5 and 7 of this gene. They found positive associations in both single-SNP (intronic SNP rs1386494, P=0.0012) and haplotype (global P=0.0001) tests.

Considering our previous linkage studies that pointed to two major bipolar disorder (BP) susceptibility loci,2 including one at 12q21 (D12S82, NPL Z-all score=3.92, P<0.01), we also investigated the TPH2 gene as a putative candidate gene using a SNP-based association study on a case/control sample. We ascertained 213 individuals from the Saguenay-Lac-St-Jean region of Quebec (bipolar I, n=182; bipolar II, n=31). Control individuals (n=214) were selected among other genetic studies, ethnically matched with the case group, but without diagnosis of psychiatric history, since there is no real gain in power to diagnose controls for a disease such as BP that has a lifetime risk of around 1%.7 The analyzed SNPs were selected following a mutation screening in 16 BP individuals on all TPH2 exons and exon–intron junctions covering 5.2 kb of the genomic sequence, which were more likely to disturb protein function. Since we did not detect any polymorphism affecting the amino-acid sequence, we analyzed all the five identified SNPs, two of which were synonymous coding SNPs (TPH2E07A, TPH2E09A), and were distributed over 24 kb between exons 7 and 9 of the TPH2 gene (Table 1). All SNPs were located downstream of the SNP analyzed by Zill et al.

Table 1 Analyzed SNPs and their corresponding alleles
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References

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  6. Zill P et al. Mol Psychiatry 2004 (Epub ahead of print).

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Authors and Affiliations

  1. Neuroscience, CHUL Research Center, Ste-Foy, Quebec, Canada

    M Harvey, E Shink, M Tremblay, B Gagné, C Raymond, M Labbé & N Barden

  2. Department Ropers for Human Genetics, Max-Planck-Institute for Molecular Genetics, Neurochemistry Group and Mouse Lab, Berlin, Germany

    D J Walther

  3. Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany

    M Bader

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  1. M Harvey
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  2. E Shink
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  3. M Tremblay
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  6. M Labbé
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  8. M Bader
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  9. N Barden
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Correspondence to N Barden.

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Harvey, M., Shink, E., Tremblay, M. et al. Support for the involvement of TPH2 gene in affective disorders. Mol Psychiatry 9, 980–981 (2004). https://doi.org/10.1038/sj.mp.4001557

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