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Lack of association of TPH2 exon XI polymorphisms with major depression and treatment resistance

Molecular Psychiatry volume 10, pages 976–977 (2005)Cite this article

Sir—A recent report in Neuron by Zhang et al (2005) presented evidence for a role in unipolar depression of the G1463A polymorphism in the 11th exon of the tryptophan hydroxylase 2 (TPH2) gene. Of special interest is their finding that seven of the nine unipolar depressed subjects carrying the rare 1463A allele were resistant to SSRI treatment. This association strongly suggested that this single-nucleotide polymorphism (SNP) is involved in major depression. We found no evidence of variation of the G1463A SNP via sequencing analysis in 182 patients with unipolar depression (of which 83 were treatment resistant), 186 nondepressed controls, and eight bipolar patients. We also report for the first time, the absence of nucleotide variation in a clinical population of two other SNPs in exon XI of the TPH2 gene (C1487G and T1578G).

The G1463A SNP results in an R441H amino-acid change in the TPH2 protein and has an 80% loss of function in serotonin production in PC12 cells.1 Zhang et al (2005) investigated this SNP in a clinical population and found that the rare allele (A) frequency was 0.9% in controls (1AA, 2AG, 216GG) and 6.9% in patients with unipolar major depression (3AA, 6AG, 78GG). The striking difference in 1463A allele frequency between the unipolar depressed group and control subjects was highly suggestive of a role for this polymorphism or this genomic region in major depression. Furthermore, in the Zhang et al's1 sample (N=306), the phenotype of seven of the nine unipolar depressed patients that carried the rare A allele were considered resistant to SSRI treatment, and the two remaining subjects were reportedly responsive to high SSRI doses. The high frequency of this rare allele and the endophenotype in which it was detected was highly suggestive of a role for TPH2 in treatment-resistant major depression. For this reason, we analyzed this SNP in 83 treatment-resistant unipolar depressed patients, eight treatment-resistant bipolar depressed patients, 99 nontreatment-resistant unipolar depressed patients and 186 control subjects without personal history of major affective disorders, using the same method described in Zhang et al (2005). Our sample population had a similar ethnic and gender distribution as Zhang et al (2005) and consisted of 67% (N=252) female, 84.1% (N=312) Caucasian, 6.2% (N=23) Hispanic, 4.6% (N=17) Asian, 2.7% (N=10) African American, 1.3% (N=5) Native American and 1.1% (N=4) Middle Eastern subjects (all unrelated). Given the genotype frequencies in the previous study, we expected at least two AA and five AG genotypes in the treatment-resistant depression group alone, and at least six AA and 12 AG if the unipolar depression groups are combined (antidepressant responsive and resistant). Surprisingly, no variation at this locus was detected in any of the subjects. To confirm our gel-based genotyping findings, we sequenced all the samples for this genomic region and in so doing were able to analyze two other reported SNPs (see Table 1). One was reported in mouse models to result in a 40% decrease in the serotonin concentrations in both the frontal cortex and striatum of BALB/cJ mouse strains when compared to 129X1/SvJ mouse strains.2 The corresponding position of this functional SNP in humans is P449R, resulting from a C1487G variation. A third SNP in this region is reported in dbSNP as rs7488262 and is a nonsynonymous change of T1578G and results in a D479E amino-acid change.3 To the best of our knowledge, neither of these two SNPs has been reported in a clinical population to date.

Table 1 SNP locations, and nucleotide and amino-acid changes of analyzed TPH2 variants
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References

  1. Zhang X et al. Neuron 2005; 45: 11–16.

  2. Zhang X et al. Science 2004; 305: 217.

  3. http://www.ncbi.nlm.nih.gov/projects/SNP/.

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Authors and Affiliations

  1. Genetics/Psychiatry, University of Arizona, Tucson, AZ, USA

    H A Garriock, J J B Allen, P Delgado, Z Nahaz, M A Kling, L Carpenter, M Burke, W Burke, T Schwartz, L B Marangell, M Husain, R P Erickson & F A Moreno

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  1. H A Garriock
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  2. J J B Allen
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  3. P Delgado
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  4. Z Nahaz
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  5. M A Kling
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  6. L Carpenter
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  7. M Burke
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  8. W Burke
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  9. T Schwartz
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  10. L B Marangell
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  11. M Husain
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  12. R P Erickson
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  13. F A Moreno
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Correspondence to H A Garriock.

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

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Garriock, H., Allen, J., Delgado, P. et al. Lack of association of TPH2 exon XI polymorphisms with major depression and treatment resistance. Mol Psychiatry 10, 976–977 (2005). https://doi.org/10.1038/sj.mp.4001712

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