Analysis of the novel TPH2 gene in bipolar disorder and suicidality

Luca, Vincenzo De; Müller, Daniel J.; Tharmalingam, Subi; King, Nicole; Kennedy, James L.

doi:10.1038/sj.mp.4001531

Cited by 61 publications

(32 citation statements)

References 13 publications

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“…23 Since the discovery of the TPH2 gene in 2003, 4 14 published studies have examined possible associations between TPH2 SNPs and various mental disorders including major depression, 17,24,25 bipolar disorder, 26 anxiety disorders, 27,28 attention-deficit/ hyperactivity disorder (ADHD), 29,30 autism 31 or suicidal behavior. 17,[32][33][34][35][36] The results of these studies have been mixed, with nine studies showing weak, but statistically significant associations between one or more TPH2 SNP and a specific mental disorder, 17,[24][25][26][27][29][30][31][32] and five showing no significant associations. 28,[33][34][35][36] Most of the studies reporting negative results failed to detect statistically significant associations for SNPs in the putative promoter region or intronic SNPs in the 5 0 -end of the gene.…”

Section: Discussionmentioning

confidence: 99%

“…17,[32][33][34][35][36] The results of these studies have been mixed, with nine studies showing weak, but statistically significant associations between one or more TPH2 SNP and a specific mental disorder, 17,[24][25][26][27][29][30][31][32] and five showing no significant associations. 28,[33][34][35][36] Most of the studies reporting negative results failed to detect statistically significant associations for SNPs in the putative promoter region or intronic SNPs in the 5 0 -end of the gene. These regions are also not associated with allelic mRNA expression observed in our study.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…[102][103][104] Further lack of replication can be found regarding suicide and major depressive disorder (MDD), even though most of the studies originate from a single group of investigators. 105,106 Other recently studied polymorphisms (rs11178997 in the promoter region of TPH2; 107 108 reported that low levels of TPH2 mRNA expression are associated with the CTGTG combination of alleles and high levels of expression with the TAAGA combination of alleles for the SNPs rs2171363, rs4760815, rs7305115, rs6582078 and rs9325202. Of these, rs7305115 is the only coding variation, although a further analysis suggested a minor role of this mutation, and the diminished concentration of TPH2 mRNA was hypothesized to be associated with a cis-acting factor.…”

Section: Tryptophan Hydroxylasementioning

confidence: 99%

Pharmacogenetics of antidepressant response

Porcelli

Drago

Fabbri

et al. 2011

J Psychiatry Neurosci

160

103

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87Personalized medicine -the adaptation of therapies based on an individual's genetic and molecular profile -is one of the most promising aspects of modern medicine. The identification of the relation between genotype and drug response, including both the therapeutic effect and side effect profile, is expected to deeply affect medical practice. In this paper, we review the current knowledge about the genes related to antidepressant treatment response and provide methodologic proposals for future studies. We have mainly focused on genes associated with pharmacodynamics, for which a list of promising genes has been identified despite some inconsistency across studies. We have also synthesized the main results for pharmacokinetic genes, although so far they seem less relevant than those for pharmaco dynamic genes. We discuss possible reasons for these inconsistent findings and propose new study designs.

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“…Some haplotype studies suggest association of the TPH2 gene to major depression (Zill et al, 2004a;Van Den Bogaert et al, 2006;Zhou et al, 2005), suicide (Zill et al, 2004c), suicide attempt (Zhou et al, 2005;de Lara et al, 2007), and bipolar disorder (Lopez et al, 2007;Harvey et al, 2004;Van Den Bogaert et al, 2006), and others disagree (De Luca et al, 2004, 2005b.…”

Section: Introductionmentioning

confidence: 99%