| 1. IntroductionMood disorder comprises two main clinical subtypes—Major depression disorder (MDD) and bipolar disorder (BPD), being one of the most popular mental disorders with unknown etiology. Published data showed MDD and BPD shared common signal pathways and genetic factors which might play important roles in the pathogenesis of the two diseases. To explore the genetic background of the specific disease would be of great value in revealing the pathogenesis of the disease and making clinical decision. Candidate-gene approach targeted in those moleculars with important biological functions had been proved to be an effective way to investigate the association of the specific gene polymorphism with specific disease.It has been proved that5-hydroxytamine(5-HT) play important role in the regulation of psychological functions, and also have close association with Mood disorder. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme for5-HT synthesis, the nucleotide variations in the gene might lead to the dysfunction of TPH, which directly changes the expression of5-HT, resulting in abnormalities of mental activities. TPH has two isoforms, TPH1and TPH2, of these, TPH2is exclusively expressed in brain, which hints TPH2might play a critical role in regulating the expression of5-HT in brain. A group of studies have showed the association of TPH2polymorphisms with MDD and BP. However, in addition to the limitation of the sample size, differences of region and ethnic also contribute to the conflict results among different studies. Hence, it is necessary for the future research to validate with larger sample size and ethnic diversity.2. ObjectivesThis research aims in investigating the association between TPH2gene polymorphism and two subtypes of Mood disorder in a Han Chinese population. Firstly, to investigate the association and risk ratio of TPH2SNPs with MDD/BPD; Furthermore, to invistigate the association between TPH2SNPs and clinical manifestations of MDD/BPD.3. MethodsFirstly, Meta-analysis was performed respectively on the association between TPH2SNPs and MD (MDD/BPD). SNAP was used to combine different TPH2SNPs and R was used to calculate the OR and p-value of different TPH2SNPs Loci. Then, case-control studies were performed subsequently to test the association between TPH2SNPs and MDD/BPD. TPH2SNPs were discriminated by using the assay of High Resolution Melting (HRM), the TPH2SNPs in MDD were further confirmed by DNA sequencing. Finally, performing SPSS17.0package, the Hardy-Weinberg equilibrium, the distribution of the allelic and genotype frequencies among the cases and controls were analyzed by χ2test. The risk ratio was evaluated using95%confidence interval. The level of significance was p<0.05.4. Results4.1Meta-analysis of the association between TPH2SNPs and MDDFor the MDD Meta-analysis,27eligible articles were found to studied a total of74single nucleotide polymorphisms (SNPs). Finally,12independent loci were included in the Meta-analysis. The synthesis of the data shown that two SNPs (rs4570625and rs17110747) were associated with MDD using fixed effects models. SNP rs4570625remained significant using the more conservative random effects calculations with a summary OR=0.83,95%CI(0.73-0.96) and low heterogeneity.4.2Association study between TPH2SNPs and MDDSix TPH2SNPs (rs17110747, rs41317114, rs7963717, rs117442844, rs41269717, rs4570625) were selected based on the results of meta-analysis on the basis of previous Meta-analysis. The case-control study confirmed the association between rs4570625and MDD in Han Chinese:There were significant differences of allele frequency and genotype distribution of this locus between MDD patients and controls (allele frequency:p=0.03, OR=0.85,95%CI (0.74,0.98); genotype:χ2=7.80,p=0.02); and the mutation of homozygote (GG) frequency is significantly higher in MDD patients with psychotic features and suicide idea than in controls, revealing the risk factor of G allele with suicide idea (OR=0.71,95%CI:0.54-0.93) and psychotic features(OR=0.62,95%CI:0.40-0.97) in MDD. We failed to identify any association of other TPH2SNPs with MDD.4.3Meta-analysis of the association between TPH2SNPs and BPDFor the BPD Meta-analysis,8eligible articles were found to study a total of54single nucleotide polymorphisms (SNPs). Finally,12independent loci were included in the meta-analysis. The synthesis of the data shown that three SNPs (rs4760820, rs11178998and rs7954758) were associated with BPD by using fixed effects models. Of these, rs4760820, rs11178998remained significant association with BPD after by using the more conservative random effects calculations with a summary (OR=0.83,95%CI:0.73-0.96) and low heterogeneity.4.4Association study between TPH2SNPs and BPDThree TPH2SNPs (rs4760820, rsl1178998, rs7954758) were selected according to the previous meta-analysis. The case-control study confirmed the association of rs4760820and rs11178998with BPD in Han Chinese:There were significant differences of allele frequency and genotype distribution of rs4760820(allele frequency:p=0.02, OR=0.64,95%CI (0.45,0.91); genotype:x2=6.84,p=0.03) and rs11178998(allele frequency:p=0.04, OR=1.45,95%CI (1.02,2.08); genotype:χ2=5.26, p=0.07) between BPD patients and controls; The mutation of rs4760820CG genotype frequency is significantly lower in BPD patients with type I (χ2=8.45,p=0.02), suicide attempts(χ2=9.11,p=0.01) and psychotic features(χ2=7.55,p=0.02) than in controls; There was significant higher G allele frequency of rs11178998in BPD patients with earlier disease onset(allele frequency:p=0.04, OR=1.68,95%CI (1.12,2.53), BP I (allele frequency:p=0.02, OR=2.06,95%CI (1.31,3.23) than in controls. We failed to identified any association of rs7954758with BPD.5. Conclusions(1) The current study further identified the association of TPH2gene SNPs with mood disorder (MDD and BP) in Han Chinese.(2) There were association between TPH2SNPs rs4570625and MDD. Of these, the G allele frequency and the GG genotype of rs4570625were significant higher in MDD patients with psychotic features and suicide idea than in controls, rs4570625might be the functional locus and need further investigation.(3) There were association between TPH2SNPs rs4760820/rs11178998and BPD. Of these, the G allele frequency of rs4760820were significant lower in BPD I patients and those with psychotic features and suicide idea than in controls, which prompted that G allele might be the protective locus, while the C allele might be the risk locus in BPD; the G allele frequency and the AG genotype of rs11178998were significantly higher in BPD I patients and those age of onset was younger than25years than in controls, rs11178998might be the functional locus, and further research were needed on the above two loci. |
PDF Full Text Request