The Relationship Between Childhood Maltreatment And Depressive Disorder In Adolescent ——Gene Expression As A Mediator

Depressive disorder is a complex psychiatric disorder characterized by persistent emotional depression,low self-esteem,anhedonia,and disrupted sleeping,eating,and cognition.Depressive disorder has become the leading cause of disability worldwide.Adolescence is a key period of the development of depression.There are obvious differences in clinical symptoms,neurophysiology characteristics,and treatment responses between adolescent and adult patients.Although the etiology of depressive disorder involves genetic and environmental factors,the underlying mechanisms remain poorly understood.Environmental stressors,such as childhood maltreatment,have been recognized to contribute to the development and progression of depressive disorder.While the mechanisms that mediate this association at the biological level have yet to be determined,and a better understanding of the biological mechanisms by which childhood maltreatment confers depressive disorder risk might shed light on novel ways to prevent and treat depressive disorder.This study included three main goals:1)to reveal the relationship between gene expression profiles and adolescent depressive disorder at the molecular level,by conducting genome-wide RNA-seq to find differentially expressed genes and biological pathways associated with depressive disorder;and identifying the depressive disorder co-expression network module using the weighted gene co-expression networks analysis(WGCNA)tool;2)to explore the relationship between childhood maltreatment history and depressive disorder at the environmental level,identifying environmental risk factors for depressive disorder by examining the relationship between various childhood maltreatment history and depressive disorder in adolescents;3)to verify through a series of mediational models that whether childhood maltreatment history had influences on depressive disorder through the expression of genes.The present study included a total of 100 participants(age: 14-19),consisting of 50 clinically diagnosed with depressive disorder and 50 healthy controls(HC)matched for age and sex.Total RNA was extracted from the peripheral blood of the participants.The association among gene expression,childhood maltreatment and depressive disorder was investigated in adolescents via a case-control research design,which included two studies and six sub-studies.Study 1 investigated the relation between depressive disorder and gene expression by biological technologies.Sub-study 1 performed a genome-wide transcriptome of peripheral blood samples via RNA-Seq to assess differences between depressive disorder(n=10)and HC(n=10).Sub-study 2 performed a weighted gene co-expression networks analysis(WGCNA)of RNA-Seq data obtained from Sub-study 1.In the combined depressive disorder and HC groups,the dynamic tree cutting method was used to assign genes to modules through hierarchical clustering,and predicted to express the data on the low-dimensional module space.In sub-study3,participants received clinical assessment using self-reported depression with the Patient Health Questionnaire–9(PHQ-9).Peripheral blood m RNA levels of 27 candidate genes were compared betweeen depressive disorder(n=40)and HC(n=40)by quantitative real time PCR(q RT-PCR).Study 2 investigated the m RNA expression of ten genes related to inflammation,immune,and signal transduction mechanism of adolescents with depressive disorder,and tested whether a history of childhood maltreatment affects depressive disorder through gene expression.The biological mechanism of childhood maltreatment history affecting depressive disorder were investigated through three parallel sub-studies,which were respectively focused on the mediating role of the expression of stress susceptibility gene RPL26,proinflammatory cytokine TNF,immune response related genes(RSAD2,STX11,PPP1R11,ZNRD1),and signal transduction mechanism related genes(c AMP,KREMEN1,KIAA1324,TMEM63C).The findings of the current study were as following:(1)A total of 18,930 genes was sequenced by RNA-seq.GO and KEGG pathway enrichment analyses of differentially expressed genes identified several GO terms and biological pathways associated with stress,such as cell killing,inflammatory response,and immune response.This provides empirical support for stress affecting the risk of depressive disorder.(2)Eleven gene modules were identified from the co-expression network.One of the modules were significantly associated with depressive disorder after multiple comparison adjustment.Several GO terms and KEGG pathways associated with stress were identified in this module,such as cell killing,channel regulator activity,and human diseases.Six genes related to inflammation,immunity,and signal transduction were identified as hub genes.This suggested that the occurrence of depressive disorder was related to stress and immunity,consistent with existing research.(3)The results showed that blood transcript levels of ten biomarkers of c AMP,TNF,RPL26,RSAD2,STX11,PPP1R11,ZNRD1,KIAA1324,KREMEN1,TMEM63 C,differed significantly between participants with depressive disorder and HC(adjusted p < 0.05).TNF,RPL26,ZNRD1 and TMEM63C were expressed at significantly higher levels in the depressive disorder group than in HC groups.Compared with the HC group,the expression levels of RSAD2,STX11,PPP1R11,c AMP,KIAA1324,and KREMEN1 in the patients group were significantly reduced.This prompted that the upregulation of inflammatory genes and the downregulation of immune response genes were associated with the risk of depressive disorder.(4)The total scores of childhood maltreatment history and the four trauma factors of physical abuse,physical neglect,emotional abuse,and emotional neglect had a significant main effect on depressive disorder,which can positively predict the risk of depressive disorder in adolescents.Sexual abuse had no significant correlation with depressive disorder in adolescents.(5)The expression of proinflammatory cytokine(TNF)and stress susceptibility gene(RPL26)was up-regulated,resulting in depressive disorder.This study supported the path of“childhood maltreatment history?the upregulation of inflammatory genes?depressive disorder of adolescents”.The gene expression of these genes played an intermediary role in the mechanism of childhood maltreatment history affecting depressive disorder in adolescents.(6)Childhood maltreatment history could lead to immune disregulation by affecting the way of immune-related genes expression(PPP1R11,RSAD2,STX11,ZNRD1),resulting in the occurrence of depressive disorder.The results supported the “childhood maltreatment history?the downregulation of immune response-related genes?depressive disorder of adolescents” path.The total indirect effect of the expression of these four genes played an intermediary role in the mechanism of childhood maltreatment history affecting depressive disorder in adolescents.(7)Childhood maltreatment history lead to depressive disorder by affecting the expression of signal transduction mechanism related genes(c AMP,KIAA1324,KREMEN1,TMEM63C).This study supported the path of “childhood maltreatment history?genes expression variation of signal transduction mechanism?depressive disorder of adolescents”.The total indirect effect of the expression of these four genes played an intermediary role in the mechanism of childhood maltreatment history affecting depressive disorder in adolescents.In summary,the conclusions are as follows: the current study including environmental factors(childhood maltreatment)and genetic factors(gene expression)enriched the understanding of the etiology of depressive disorder in adolescents.The results supported a role of inflammation,immune,and signal transduction as potential effectors of environmental stress in depressive disorder.Childhood maltreatment history impacted the probability of depressive disorder by affecting gene expression.The total effect of the three sets of gene expression as an intermediary variable regulated the association between childhood maltreatment history and the risk of depressive disorder,suggesting that gene regulation in adolescent depressive disorder is the aggregation effect of multiple genes.Thus,a better understanding of the biological mechanisms that lead to depressive disorder risk from childhood maltreatment history might shed light on novel ways to prevent and treat depressive disorder.