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

Garriock, Holly A.; Allen, John J. B.; Delgado, Pedro R.; Nahaz, Z.; Kling, Mitchel A.; Carpenter, Linda L.; Burke, M.; Burke, William J.; Schwartz, Tamar; Marangell, Lauren B.; Husain, Mohammad; Erickson, Robert P.; Moreno, Francisco

doi:10.1038/sj.mp.4001712

Cited by 53 publications

(30 citation statements)

References 8 publications

(10 reference statements)

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“…Since the discovery of the tryptophan hydroxylase 2 (TPH2) isoenzyme (Walther et al, 2003)Fthe rate-limiting enzyme of 5-HT synthesis in the brainFTPH2 polymorphisms in humans have been associated with anxiety traits, depressive disorders, and suicidality (Gutknecht et al, 2007;Reuter et al, 2007;Van Den Bogaert et al, 2006;Zhang et al, 2005;Zill et al, 2004a, b) yet these results have not been supported by other studies (De Luca et al, 2006;Garriock et al, 2005;Juhasz et al, 2010;Mann et al, 2008;Middeldorp et al, 2010). These discrepancies might be partially attributed to the fact that different SNPs in the TPH2 gene were analyzed.…”

Section: Introductioncontrasting

confidence: 37%

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Berger

Weber

Perreau-Lenz

et al. 2012

Neuropsychopharmacol

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The association of single-nucleotide polymorphisms (SNPs) in the human tryptophan hydroxylase 2 (TPH2) gene with anxiety traits and depression has been inconclusive. Observed inconsistencies might result from the fact that TPH2 polymorphisms have been studied in a genetically heterogeneous human population. A defined genetic background, control over environmental factors, and the ability to analyze the molecular and neurochemical consequences of introduced genetic alterations constitute major advantages of investigating SNPs in inbred laboratory mouse strains. To investigate the behavioral and neurochemical consequences of a functional C1473G SNP in the mouse Tph2 gene, we generated congenic C57BL/6N mice homozygous for the Tph2 1473G allele. The Arg 447 substitution in the TPH2 enzyme resulted in a significant reduction of the brain serotonin (5-HT) in vivo synthesis rate. Despite decreased 5-HT synthesis, we could detect neither a reduction of brain region-specific 5-HT concentrations nor changes in baseline and stress-induced 5-HT release using a microdialysis approach. However, using a [ 35 S]GTP-g-S binding assay and 5-HT 1A receptor autoradiography, a functional desensitization of 5-HT 1A autoreceptors could be identified. Furthermore, behavioral analysis revealed a distinct anxiety phenotype in homozygous Tph2 1473G mice, which could be reversed with chronic escitalopram treatment. Alterations in depressive-like behavior could not be detected under baseline conditions or after chronic mild stress. These findings provide evidence for an involvement of functional Tph2 polymorphisms in anxiety-related behaviors, which are likely not caused directly by alterations in 5-HT content or release but are rather due to compensatory changes during development involving functional desensitization of 5-HT 1A autoreceptors.

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Section: Introductioncontrasting

confidence: 37%

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Berger

Weber

Perreau-Lenz

et al. 2012

Neuropsychopharmacol

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“…Nazree et al, recently reported lack of association between TPH2 gene polymorphism with major depressive disorder in three ethnic groups of Indian, Chinese and Malaysian population [13]. Similar findings have been reported by Garriock et al, who also observed lack of association of TPH2 polymorphisms with major depression and treatment resistance [14]. However our findings are in contrary to Tsai SJ et al, who recently observed that TPH2 genetic variants may play a role in MDD susceptibility [15].…”

Section: Methodscontrasting

confidence: 57%

Tryptophan Hydroxylase 2 Gene Polymorphism in Anxiety and Depressive Disorder in Kashmiri Population

Mushtaq

Shoib

Shah

et al. 2014

JCDR

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Background: The gene of tryptophan hydroxylase is widely recognized as a major candidate gene in many psychiatric disorders. However, no study has been done which investigates tryptophan hydroxylase 2 gene polymorphism in anxiety and depressive disorders in Kashmiri population (India).Objectives: To study tryptophan hydroxylase 2 (TPH2) C 11993 A gene polymorphism in anxiety and depressive disorders.Method: Sixty patients of depression disorder, 60 patients of anxiety disorder and 40 unrelated healthy volunteers (control) were studied in a case control design. Polymorphism was determined using polymerase chain reaction (PCR) and agarose gel electrophoresis after digestion with HAP II enzyme. Genotypes and allele frequencies were compared using Chi-square tests, Fischer's exact test, odds ratio, 95% confidence interval (C.I) and p-value of <0.05 was considered to be statistical significant. Results:The mean age ± SD of anxiety, depression and control group was 32.73±10.99, 32.20±10 and 29.75±10.12 respectively and the difference was found to be statistically non significant (p=0.349).The mean HAM-A (Hamilton rating scale for anxiety) score and HAM-D (Hamilton rating scale for depression) score was high in both groups (anxiety and depression) and found to be statistically significant (p=0.001).Depression group had AA genotype (55.2%) than control (37.5%) and was found to be statistically non significant (p=0.890).Comparison of allelic frequency revealed no association of A allele in anxiety group (76.67%) compared with control (75.5%) and was found to be statistically non significant (p= 0.866), OR 1.09 (0.56-2.11).Conclusion: TPH2C 11993 A gene was not found to be associated with major depressive disorder (MDD) and anxiety disorder in Kashmiri population.

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“…8,[37][38][39][40] Among the remaining eight studies reporting an association between TPH2 SNP alleles and a mental disorder, four found statistically significant associations for SNPs within the region comprising introns 5-8.…”

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

Cited by 53 publications

References 8 publications

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Tryptophan Hydroxylase 2 Gene Polymorphism in Anxiety and Depressive Disorder in Kashmiri Population

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

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