Association Between The 5-HT Pathway Related Genes And Mood Disorders

PARTâ… Association between the 5-HT_2Apathway related genes and mood disordersObjective:This research aims at the investigating the association between 5-HT2A pathway related genes,including G protein,adenylcyclase, phosphodiesterase or cAMP responsive element binding protein,and mood disorders.Also,the effects of the gene x gene interaction on the risk of mood disorders will be investigated.Methods:(1)With the case-control design,417 mood disorders and depressive disorder patients(326 depressive disorder patients,91 mood disorder patients),met the criteria of DSM-â…£and CCMD-3,and 293 healthy Chinese Han were recruited in Henan Province,and respectively compared distributional difference of genotype and allele between two groups,and analyzed association between SNP_s and mood disorders.(2)Five SNPs of 5-HT2A rs6311,GNβ3rs5443,ADCY9rs2230739, PDE1Ars1549870,which were located at the genes of 5-HT_2Apathway, were discriminated by using the assay of LDR.(3)Performing SPSS 11.5 package,the Hardy-Weinberg equilibrium, the distribution of the allelic and genotype frequencies among the cases and controls were analyzed by x² test.The morbidity risk was evaluated using 95%confidence interval,odds ratio and confidence interval.The level of significance was p=0.05.Results:1.The polymorphism of the five SNPs::There were polymorphism of rs6311,rs5443,rs2230739 and rs 1549870,and no polymorphism of CREB1 rs255163 among these 710 Chinese Han(417 patients with mood disorders and 293 healthy controls).2.Comparison of genotypic/allele frequency between patients and controls:Genotypic frequencies of the wild-type homozygote(TT),TC and the mutation homozygote(CC)of rs6311 among 417 patients with mood disorders were 0.316,0.494 and 0.19 respectively,T allel frequency was 0.563,and C allel frequency was 0.437.Correspondingly in 293 healthy controls,genotypic frequencies of TT,TC and CC were 0.433, 0.430 and 0.137 respectively,T allel frequency was 0.648,and C allel frequency was 0.352.There was significant difference of genotypes distribution of rs6311 between patients and controls.The mutation homozygote(CC)frequency is significantly higher in patients than in controls,but the wild-type homozygote(TT)frequency is lower (x²=11.003,p=0.004).Also the T allele frequency was lower and the C allelic frequency is higher in the patients(OR=1.434,95%CI=1.153～1.783;x²=10.523,p=0.001).As for rs5443,its genotypic frequencies of TT,TC and CC in 417 patients were 0.18,0.472 and 0.348 respectively,T allel frequency was 0.416,and C allel frequency was 0.581. Correspondingly in healthy controls,its genotypic frequencies of TT, TC and CC were 0.119,0.515 and 0.365 respectively,T allel frequency was 0.433,and C allel frequency was 0.567.There were significant difference in neither genotype nor allel distribution between patients and controls(p＞0.05).Genotypic frequencies of GG,GA and AA of rs 2230739 among 415 patients with mood disorders were 0.176,0.498 and 0.335 respectively,G allel frequency was 0.563,and A allel frequency was 0.437.Correspondingly in 293 healthy controls,genotypic frequencies of GG,GA and AA of rs2230739 were 0.119,0.515 and 0.365 respectively,G allel frequency was 0.377,and A allel frequency was 0.632.There was no significant difference of genotype\allel distribution between patients and controls(p＞0.05).As for rs1549870,its genotypic frequency of GG,GA and AA among 408 patients were 0.49,0.426 and 0.083 respectively,G allel frequency was 0.703,and A allel frequency was 0.297.Correspondingly in healthy controls,its genotypic frequencies of GG,GA and AA were 0.557,0.361 and 0.082 respectively,G allel frequency was 0.737,and A allel frequency was 0.263.There were significant difference in neither genotype nor allel distribution between patients and controls(p＞0.05)3.Comparison of genotypic and allele distribution of SNPs in different subtypes:There were significant difference in three genotype interclasses of rs6311 by comparing between control group and depressive group(326 cases,134 males,192 females).In depressive group, not only TT obviously decreased,while CC mcreased(x²=6.460,p-0.04), but also T allele frequency of depressive group was lower,while C allele frequency was higher in depressive group(OR=1.360,95%CI=1.080～1.712;x²= 6.865,p=0.009);There were no significant difference of genotypic \allele distribution of rs5443,rs2230739 and rs1549870 among interclasses(p＞0.05),and no significant difference genotypic\allele distribution of four SNPs in interclasses between male group and female group also(p＞0.05)However,there were significant difference distribution of rs6311 in three genotype interclasses between 117 healthy controls and 91 patients with bipolar mood disorders.TT frequency is significantly higher in patients than in controls,but GG frequency is lower(x²= 11.031,p=0.004),and there were no significant difference of genotype frequencies in other gene locuses between two groups(p＞0.05). T allele frequency of bipolar mood disorder group was lower,but C allele frequency was higher than control group(OR=1.735,95%CI = 1.168-2.578;x²=7.504,p =0.006).There were no significant difference of other SNPs between two groups(p＞0.05)4.Association analysis between SNPs genotypes and mood disorders:The relative risk of rs6311 CC genotype was(OR=1.487, 95%CI=0.983～2.249,x²=3.561,p=0.059),and that of TT was(OR =1.659,95%CI=1.216～2.262;x²=10.287,p=0.001).The genotype frequencies of rs5443 TT,rs 5443 TC,rs 2230739 AA,rs 2230739GA and rs 1549870 GG is trendily higher in patients.However,there were no significant difference(p＞0.05).Regression analysis was performed to inVestigate the effects of the four SNPs genotypes on mood disorders.We found that TT and TC of rs 6311 entered equations,and their regression coefficient were -0.618 and -0.161 respectively.5.The sick combination risk of RS6311 with other SNPs genetypeWhen TT of rs6311 combined with CC of rs5443 or CC of rs6311, the sick risk would be increased,especially CC of rs6311 with TT or CC of rs5443[(OR=4.838,95%CI=1.091～21.450;x²=5.237,p=0.022) or(OR=3.329,95%CI= 1.703～6.510;x²=13.662,p=0.000)];When CC of rs63 combined with GG of rs 2230739,the sick risk would be increased(OR=3.375,95%CI=0.961～11.851,x²=4.046,p=0.044); When CT of rs6311 combined with AG of rs1549870,the sick risk was increased(OR=1.645,95%CI=1.107～2.444,x²=6.313,p=0.013),too.Conclusions:1.The SNP of rs6311,located in 5-HT2A,associates with the mood disorders in Chinese Han.It also has the association with the depressive disorder and the bipolar affective disorder.The gene mutation of rs6311 would lead to mood disorder directly perhaps or there were virulence gene near the genetic locus possibly.We could reach the conclusion that the CC genotype carrier suffer from higher risk of the onset of the disorders,while T allele carrier lower risk.On the other hand,since there is no evidence that the rs6311 affects the expression of the 5-HT_2Agene, the results on rs 6311 might suggest that there is another functional locus near it.Therefore,it is worthy to undergo the detail investigation.2.Both rs 5443 in GNB3 and rs 2230739 in ADCY9 are high allelic frequency SNPs in Chinese Han.When CC of rs6311 combined with Tr or CC and with GG of rs 2230739,the sick risk is increased obviously, although there is no evidence for association between them and mood disorders.The two SNPs allele located at coding region,so GNβ3 and ADCY9 may be the minor genes on mood disorders.3.No proofs were found that there were association between PDE1Ars1549870 and mood disorders.4.No polymorphism of rs 2551638 in CREB1 among Chinese Han was found,so we can not infer whether CREB is related to mood disorders. PARTâ…¡Association between Polymorphisms of the Genes Related to 5-HT_2APathway and Phenotypes of Major Depression DisorderObjective:To investigate the relationship between four SNPs located in the genes related to 5-HT_2Apathways and symptoms of major depression disorder(MDD)and the association of the SNPs with MDD.Methods:A total of 194 patients with major depression disorder(MDD)were recruited in this study.According to DSM-â…£and CCMD-â…¢criteria,the symptoms,episode of tendency,and psychotic symptoms were scaled.Among 194 patients with MDD,the SSRIs treated outcome was evaluated in an open-trail study.174 out of them were followed up longer than one year while the optimal scaling was used to investigate the association between different genotypes of the SNPs and phenotypes, such as the symptoms and the outcome with SSRIs treatment.Results:1.Relationship between four SNPs and fundamental symptomsThe Multiple Correspondence Analysis shows the strong association between the four SNPs and the symptoms of MDD.The genotypes of rs6311CC,rs5443CC,and rs1549870GG are relatively closed to the symptom 2 in the same block.The distance from rs5443CC and rs1549870GG to the symptom 2 is the shortest.The genotypes of rs5443CT,rs1549870AG and rs2230739AG are in the same zone. Although the distances between the three SNPs are short,no association between them and the fundamental symptoms of MDD or suspected depressive mood was found.2.Relationship between four SNPs and accessory symptomsThe Multiple Correspondence Analysis also shows the association between the four SNPs and the accessory symptoms.The genotype of rs6311CC and accessory symptoms 7(suicidal thoughts and acts)are in the same zone,because the distance between them is the shortest. However,the genotype rs6311TT and the non-suicide are in the same block and stay very close.The distance between rs6311CC and symptoms, including insomnia and cognitive symptoms,is relative short.The rs5443CT and the rs1549870AG associate with fatigue symptoms.3.Relationship between four SNPs and other clinical charactersThe Multiple Correspondence Analysis shows the association between the four SNPs and other clinical characters.The rs6311CC and depressive episode with psychotic symptoms and relapse are in the same block.The genotype rs6311Tr predicts less relapses of MDD because both of them are in the same block.The rs1549870GG and depression without psychotic symptoms are in the same zone and near.4.Relationship between the four SNPs and the long-term outcome with SSRIs treatment.Two SNPs of rs5443 and rs2230739 associated with short-term outcome with SSRIs treatment.The coefficients of regression are 0.181 and 0.283,respectively.The rs2230739GG predicts the good long-term outcome with SSRIs treatment.The coefficient of regression is 0.400.Conclusion:1.The rs6311CC strong associates with depressive symptoms, including loss of interest and pleasurable feeling,suicide,insomnia, psychotic symptoms and relapse tendency.It suggests that rs6311 may be a functional SNP affecting the expression of the 5-HT_2Agene.It remains unclear whether the polymorphism of rs6311 is the genotype of depression or not.2.The rs5443TT(Gβ₃)and rs2230739GG(ACDY₉)carriers have better short-term response to SSRIs.It is presumed that different genotypes of rs5443(Gβ₃)and rs223073(ADCY₉)can modulate the second message signal conduction pathways,and therefore lead to different response.3.The rs2230739GG(ADCY₉)carriers have better long-term respponse to SSRIs.We may conclude the polymorphism of rs2230739 (ADCY₉)may be the biological basis for the inter-individual different response.