Association Analysis Between TPH2 And Severe Mental Illnesses And The Association Of HTR1A And HTR2A Genes With Antidepressant Efficacy

Schizophrenia(SCZ)and Major depressive disorder(MDD)are complex diseases with highly heritability and recurrent episodes.So far,the pathogenesis of the above two major mental illnesses has not been clarified.In addition,there are also large individual differences in drug treatment based on the existing onset hypothesis.There is evidence that serotonin pathway metabolism is associated with the pathogenesis of SCZ and MDD,and that this pathway is also a target for a variety of antidepressant treatments.In this paper,we selected three genes TPH2,HTR1 A and HTR2 A in the serotonin signaling pathway to conduct the following studies.The first part of the dissertation is about the association analysis between TPH2 gene polymorphism and Chinese Han SCZ patients.We recruited 1034 SCZ patients and 1034 normal controls,and performed a case-control study on three single nucleotide polymorphisms rs1007023,rs1023990 and rs4570625.No significant associations with SCZ were found by comparing allele and genotype distribution in both gender stratification analysis and five genetic model analyses.The second part of the dissertation is to test whether the TPH2 gene polymorphisms are related to MDD and the functional study of rs4570625.A total of 459 MDD patients and 784 normal controls were collected from Chinese Han population,and case-control studies were performed on three SNPs of TPH2 gene.We found genotype(P = 0.012)and allele(P = 0.012)distribution of rs1023990 were significant differences between the two groups.In the linkage disequilibrium analysis,there was a strong linkage between rs1023990 and rs4570625,and haplotype rs1023990-rs4570625 T-G showed weak association with MDD(P = 0.046).Five genetic model analysis of the selected SNPs were performed by R software.We found the codominant model(P = 0.014)recessive model(P = 0.004)and log-additive model(P = 0.012)of rs1023990 were significant;rs4570625 showed significant result in the dominant model(P = 0.031).The above studies suggested that TPH2 may be a susceptible gene for MDD.Based on the above results,we selected the functional site rs4570625 of promoter region for functional verification test.By constructing plasmid vectors and transfecting into HRK293 T cells,it was found that the G>T mutation on rs4570625 did not cause a difference in the expression level of the luciferase reporter gene.The third part of the dissertation is the association study between HTR1 A and HTR2 A genes and venlafaxine treatment in Chinese Han MDD patients.We recruited 175 MDD patients,which were divided into responder/non-responder and remission/non-remission according to both the subtraction rate method and the sixth week score of the depression scale.Demographic analysis and statistical analysis were used to by SHEsis,R software and Haploview,the co-dominant model(P = 0.0426)and overdominant model(P = 0.0121)of HTR2 A gene rs6311 were both significant in the remission and non-remission groups.This suggests that HTR2 A may be associated with the efficacy of venlafaxine in the treatment of MDD patients.