The Relationship Between Psychotic Depression With Multiple Gene Mutations Of CAMP Pathway

Objectives1.To investigate the clinical characteristics of psychotic depression for early clinical recognition.2.To analyze the relationship between psychotic depression with tagSNPs and rare variants of gene in cAMP pathway for its genetic markers.Methods1.According to the diagnostic criteria of major depressive disorder in DSM-IV,a total of 1182 patients were included,the diagnosis of 1022 major depressive disorder patients remained unchanged after more than 4 years of follow-up,and grouped them according to whether the total score of BPRS positive symptom items was≥9,include 176 psychotic depression patients(hereinafter referred to as the PD group)and 846 non-psychotic depression patients(hereinafter referred to as the NPD group),compared the social demographic data and clinical characteristics between the two groups.2.Genotyping of nine tagSNPs in six genes(HTR1A rs878567,HTR2A rs1328683、rs17068986、rs3125、ADCY3 11676272、ADCY7rs1064448、CREB1 rs2551645、rs3770704、BDNF rs10835210)of gene in cAMP pathway was performed on the samples from 1022 major depressive disorder patients(176 PD patients,846 NPD patients)using Sequenom mass spectrometry,compared the distribution differences of nine tagSNPs genotypes and allele frequencies between the two groups,and analyzed the gene-gene interactions of nine tagSNPs.3.Eight genes related to the cAMP pathway(HTR1A、HTR2A、ADCY3、ADCY7、CREB1、BDNF、SLC6A4、PDE4D)were selected as the target genes,detecting rare variants in 427 major depressive disorder patients included at a later stage which the diagnosis remained unchanged after more than 4 years of follow-up by High-throughput sequencing(92 PD patients,335 NPD patients),compared the distribution differences of rare variants alles and cumulative burden between the two groups.4.Statistical analysis:SPSS 22.0 statistical software package were used for statistical analasis.Qualitative data were expressesd as percent(%)and analyzed by chi-square(χ2).Quantitative data were tested by K-S test,the data which accord with normal distribution were expressed as mean±standard deviation(X±S)and analyzed by T-test,the data which don not accord with normal distribution were expressed median(quartile)and analyzed by non-parametric test(Mann-Whitnry).Analyzed the distribution differences of rare variants alles and cumulative burden between the two groups by chi-square(χ2)or Fisher exact test(The latter is used when the desired frequency is small than 5),Calculateed OR and 95%CI.The generalized multifactor dimension reduction(GMDR)BetaV0.7 software package was used to analyze the gene-gene interaction.P<0.05 was considered statistically significant.Results1.Comparison of socia-demographic data and clinical characteristics between the two groupsSocia-demographic data and clinical characteristica were compared between the PD group and NPD group,the age and oneset age of PD group is smaller than NPD group(t=2.367,P=0.018;t=3.215,P=0.001),there were statistically significant differences between the two groups in the family history of mental disorders and the suicidal ideation(χ2=4.454,P=0.035;χ2=4.512,P=0.034).There was no significant difference between the two groups in gender composition,marriage,educational level,frequency of attacks,cause of oneset,and seasonal characteristics(P>0.05).2.Factors of psychotic depressionMultivariate Logistic regression analysis found that the influencing factors of psychotic depression were in order:family history of mental disorders(P=0.043,OR=1.418,95%CI:1.010～1.990),and age of onset(P=0.045,OR=0.973,95%CI:0.947～0.999).3.The distribution of tagSNPs in six genes genotypes and alleles frequency was compared between the two groupsThe distribution of genotypes and alleles frequency of nine tagSNPs in six genes of HTR1A、HTR2A、ADCY3、ADCY7、CREB1and BDNF were compared between the two groups,there was significant difference in allele frequency of HTR2A rs17068986 between two groups(χ2=4.700,P=0.030),the frequency of T allele in PD group than in NPD group(61.9%vs 55.5%,OR=1.301,95%CI:1.025～1.652);there was significant difference in allele frequency of BDNF rs10835210 between two groups(χ2=3.912,P=0.048),the frequency of A allele in PD group than in NPD group(31.0%vs25.8%,OR=1.297,95%CI:1.002～1.679);there was no significant difference in genotype of HTR2A rs17068986 and BDNF rs10835210 between two groups(P>0.05);there was no significant difference in genotype and allele frequency of the ather seven tagSNPs(HTR1A rs878567,HTR2A rs1328683、rs3125、ADCY3 11676272、ADCY7 rs1064448、CREB1 rs2551645、rs3770704)(P>0.05).4.Gene-gene interaction analysisGMDR analysis showed that the three-locus model(HTR2A rs1328683,rs17068986,ADCY3 11676272)had statistical significance(P=0.011,1000 permutation tests),this model was the best model,the cross-validation consistency was 9/10,and the test accuracy was 0.561.There was no significant difference of the one-locus,two-locus and more than three-locus(P>0.05,1000 permutation tests).5.Comparison of alleles frequency distribution of rare variants in eight genesThe alleles frequency of 68 rare variants related to eight genes of HTR1A,HTR2A,ADCY3,ADCY7,CREB1,BDNF,SLC6A4 and PDE4D were compared between the two groups,it was found that the distribution of allele frequency of SLC6A4 rs6352 between the two groups was statistically significant(P=0.016),the G allele frequency of PD group was higher than that of NPD group(OR=2.291,95%CI:1.149～4.568).Moreover,this site was predicted to be pathogenic by Mutation taster functional prediction software.There was no significant difference in the allele frequency distribution of other rare variants between the two groups(P>0.05).6.The cumulative burden of eight gene rare variants was compared between the two groupsThe distribution of cumulative burden rare variants of HTR1A,HTR2A,SLC6A4,ADCY3,ADCY7,PDE4D,CREB1 and BDNF genes were compared between the two groups,the distribution of rare variants cumulative load of SLC6A4 genes in the two groups was statistically significant(17.4%vs 9.0%,P=0.021).There was no statistically significant difference in the cumulative load of other rare gene variants between the two groups(P>0.05).Conclusions1.psychotic depression patients is associated with an earlier onset age,a more frequent association with a family history of mental disorders and suicidal ideation,suggesting that the genetic tendency of psychotic depression patients is higher and the prognosis is worse.2.The susceptibility risk of psychotic depression in T allele carriers of HTR2A rs17068986 and the A allele carriers of BDNF rs10835210 is higher than the C allele carriers,suggesting that HTR2A rs17068986 and BDNF rs10835210 may be the susceptibility locus of psychotic depression.3.There is a gene-gene interaction between the HTR2A and ADCY3 genes and can increase the susceptibility of psychotic depression,suggesting that HTR2A and ADCY3 gene are the minor gene of psychotic depression.4.Rare variants of SLC6A4 gene are associated with psychotic depression,and rs6352 may be the rare pathogenic site.