Imaging Genetics Studies Of Major Depressive Disorder Based On Single Gene And Pathway Genes

BackgroundMajor depressive disorder(MDD)is a mental disorder characterized by low mood,delayed thinking and decreased mental activity.It affects about 350 million people worldwide.The disease often recurs and has become a major mental disorder affecting human physical and mental health.The world health organization expects MDD to rise to the top of the overall global burden of disease by 2030.The exact pathogenesis of depression is still unknown.The current diagnostic criteria are mainly based on patients’ clinical symptoms and lack of clear biological diagnostic criteria,so the diagnostic consistency is low.The determination of reliable biological diagnostic markers is a problem that researchers have been paying close attention to and constantly exploring.More importantly,the current treatment of MDD still has problems such as slow onset,large individual differences and low overall response rate.The ability to predict whether a patient will respond to an antidepressant before taking the drug,especially the early prediction of antidepressant efficacy,may contribute to the selection of clinical drug or timely adjustment of medication strategies to improve clinical efficacy.To sum up,the search for reliable and stable clinical markers for diagnosis and treatment has become an important issue that urgently needs to be solved.As a complex disease,the heritability of MDD is about 31～42%.Although there are many genetic studies on MDD at present,no definite pathogenic gene has been found.Because genetic effects are not simply expressed at the behavioral level,in other words,they do not translate directly into disease phenotypes.Therefore,a mediating phenotype has been proposed as a stable trait linking genetic factors to disease phenotypes.With the help of neuroimaging technology,the influence of genetic factors on the phenotype of disease is discussed with the brain structure or function as the mediating phenotype,which is called imaging genetics.In an exploratory study looking for a potential phenotype mediated by imaging genetics,our team use multiple regression analysis and find that CACNA1C gene is closely related to the gray matter network associated with anhedonia.It is demonstrated that CACNA1C significantly affects the function of monoamine systems,such as 5-hydroxytryptamine(5-HT)and dopamine(DA)energy systems,which are suggested to be most important for MDD.The onset and progression of MDD are not regulated by one or several genes.In recent years,people have begun to pay attention to the genetic pathway,among which the roles of 5-HT and DA pathways in the pathogenesis of depression have been extensively studied.If regarding the intermediate phenotypes of imaging genetics as the breakthrough point,foucs on a characteristic clinical phenotypes of the MDD such as curative effect or lack of pleasure,and comprehensively consider the indicators of genetics and neuroimaging,will contribute to a more comprehensive understanding of the important influence factors on MDD,and contribute the diagnosis and treatment for major depressive disorder in clinical practice in the future to build more practicality and maneuverability of the evaluation framework.Therefore,this study adopt the way of gradually progressive,study respectively from the following two aspects:first,based on the fidings of our previous studies that CACNA1C gene is closely related to MDD,respectively to investigate the interactive effects of depression and the single nucleotide polymorphisms(SNPs),the cumulative effects of multiple SNPs within CACNA1C gene on spontaneous brain activity and the founctional connectivities within default mode network(DMN),for the purpose to clarify the relation between MDD and CACNA1C gene,to explore the roles of brain intermediate phenotype on the pathogenesis of depression,and the prediction of curative effect.Second,based on the genetic pathway gene,two modal genetic indicators are included,namely,within the pathway(dopamine pathway,5-hydroxy try ptamine pathway)and between the pathways(DA pathway and 5-HT pathway),to further comprehensively analyze the value of gene polymorphisms on the pathogenesis and efficacy prediction of depression.Part 1.Imaging genetics studies of CACNA1C gene polymorphisms on brain function in patients with major depressive disorderChapter 1.CACNA1C gene rs11832738 polymorphism influences depression severity by modulating spontaneous activity in the right middle frontal gyrus in patients with major depressive disorderObjectives:This study aims to examine whether the CACNA1C gene rs11832738 polymorphism and major depressive disorder(MDD)have an interactive effect on the untreated regional amplitude of low-frequency fluctuation(ALFF)and to determine whether regional ALFF has an association with the depression severity in MDD.Methods:A total of 116 patients with MDD and 66 healthy controls(HCs)are recruited.The MDD and HC groups are further divided into two groups according to genotypes:carriers of the G allele(G-carrier group,GG/GA genotypes;MDD,n=61;HC,n=26)and AA homozygous group(MDD,n=55;HC,n=40).MDD is diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders,fourth edition.Depression severity is assessed using the Hamilton depression scale-24(HAMD-24).All subjects recieve functional magnetic resonance imaging(fMRI),and the ALFF is calculated to reflect the spontaneous brain activity based on fMRI data.The interactive effect between MDD and CACNA1C single nucleotide polymorphism rs 11832738 is determined using two-way factorial analysis of covariance,with age,sex,education,and head motion as covariates.We perform correlation analysis to determine whether regional ALFF strength have associations with depression severity and use mediation analysis to further determine whether regional ALFF strength could mediate the associations between rs11832738 and depression severity.Results:MDD have a main effect on regional ALFF distributed in three brain areas:the right medial frontal gyrus,the left anterior cingulate cortex,and the right cerebellum posterior lobe.CACNA1C rs 11832738 shows a interactive effect with MDD on the ALFF of right medial frontal gyrus.For CACNA1C G allele carriers,the ALFF of right medial frontal gyrus has a significantly positive correlation with the baseline HAMD-24 score.Exploratory mediation analysis reveals that the intrinsic ALFF in right medial frontal gyrus significantly mediates the association between the CACNA1C rs11832738 polymorphism and baseline HAMD-24 score.Conclusions:CACNA1C rs 11832738 may influence depression severity in MDD patients by moderating spontaneous activities of right medial frontal gyrus.Chapter 2.The multi-site cumulative effect of CACNA1C gene on anhedonia-associated brain activities in major depressive disorderObjectives:To explore whether multi-site cumulative effect of CACNA1C influences anhedonia-associated spontaneous brain activity in patients with major depressive disorder(MDD).Methods:104 patients with MDD and 64 healthy controls are recruited.Anhedonia symptom is measured using Snaith Hamilton rating scale(SHAPS).Amplitude of low-frequency fluctuation(ALFF)which reflects the spontaneous brain activity is calculated by DPARSF.Multilocus genetic profile scores(MGPS)is used to assess the multi-site cumulative effect of CACNA1C gene.The effects of MDD and CACNA1C MGPS on spontaneous brain activity are measured by multivariate linear regression analysis.And then,correlations between spontaneous activities of the influenced brain areas and anhedonia are analyzed.Results:CACNA1C MGPS significantly interacts with MDD on the spontaneous activities of six brain areas.Moreover,the ALFF of left inferior frontal gyrus has significant positive correlations with baseline SHAPS score(r=0.225,P=0.025)and 8-week SHAPS score(r=0.223,P=0.030);the ALFF of left precentral gyrus is significantly positively correlated with the 8-week SHAPS score(r=0.204,P=0.048);the ALFF of right medial frontal gyrus is significantly positively correlated with the SHAPS score reduction(r=0.217,P=0.034).Conclusions:The multi-site cumulative effect of CACNA1C could affect anhedonia-associated spontaneous frontal activities.Chapter 3.The CACNA1C gene polymorphisims on early treatment response in major depressive disorder based on default mode networkObjective:This study aims to investigate the relationship between the functional connectivities(FC)within default mode network(DMN)network and early treatment response in patients with major depressive disorder(MDD)under the influence of the multi-site cumulative effect of CACNA1C gene.Methods:Ninety-nine patients with MDD and 64 healthy controls(HCs)are recruited.We use the Hamilton depression scale-24(HAMD-24)reductive rate to measure the early therapeutic effect.The FCs within the DMN are calculated using DPARSF.The effects of cumulative effect of eight SNPs within CACNA1C are measured by multivariate linear regression analysis.Mediation analysis is performed to further determine whether FCs strength have a mediation effect between CACNA1C and treatment response in MDD.Results:In the MDD group,the FC between retrosplenial cortex(RSC)and anterior medial prefrontal cortex(aMPFC)has a negative correlation with 2-week HAMD-24 reductive rate(r=-0.207,P=0.043).Exploratory mediation analysis reveal that the FC between RSC and aMPFC has a significant mediation effect between CACNA1C MGPS and 2-week HAMD-24 reductive rate.Conclusions:Our study highlighted the predictive value of abnormal FC within DMN networks in the early treatment response in MDD.Part 2.Imaging genetics studies based on pathway genes polymorphisms in major depressive disorderChapter 4.The relationship between spontaneous brain activities and early therapeutic effect underlying 5-hydroxytryptamine pathway gene in major depressive disorderObjectives:We aim to investigate the changes in spontaneous brain activities under the interactive effect of 5-hydroxytryptamine(5-HT)pathway genes and disease,and further explore the relationship between spontaneous brain activities which are interactively effected and the early therapeutic effect of in MDD.Methods:25 patients with MDD are recruited,and they receive treatment of selective serotonin reuptake inhibitors(SSRIs)after the evaluation of depression symptoms and the scan of functional magnetic resonance imaging(fMRI).29 healthy controls are also required for the evaluation of depression symptoms and the fMRI scan.The effects of MDD and 5-HT pathway gene on spontaneous brain activity are measured by multivariate linear regression analysis.Results:The interactive brain area of 5-HT MGPS and MDD are right cerebellum posterior lobe,right insula,right putamen,right supramarginal gyrus,left postcentral gyrus,left precentral gyrus,right superior occipital gyrus,left precuneus,and left superior parietal gyrus.Among them,the activities of right insula,left precuneus,and left superior parietal gyrus are decreased,and those of other brain areas are increased.The activities of left postcentral gyrus and right putamen have significant correlations with HAMD-24 reductive rate score(r=-0.457,P=0.022;r=-0.478,P=0.016).Conclusions:The interaction between 5-HT pathway genes and MDD occurrs in multiple brain regions involved in emotion regulation,and the spontaneous activities of two brain regions,namely the left postcentral gyrus and the right putamen,may be used as markers of the early therapeutic efficacy of SSRIs.Chapter 5.Dopamine multilocus genetic profile,spontaneous activities of left superior temporal gyrus and early therapeutic effect in major depressive disorderObjectives:This study aims to examine whether the interactive effects of DA pathway gene and disease on spontaneous brain activities could influence the early therapeutic effect of antidepressant in patients with major depressive disorder(MDD).Methods:104 patients with MDD and 64 HC are recruited.The HAMD-24 is used to measure the severity of depression.Both groups are given fMRI scans.The ALFF is calculated to reflect the spontaneous brain activities based on the fMRI data.After treatments of two weeks,HAMD-24 is evaluated again,and HAMD-24 reductive rate is used to measure the therapeutic effect of antidepressants.MGPS is used to assess the multi-site cumulative effect of DA pathway gene.The interactive effects of MDD and DA pathway gene on the ALFF of regional brain areas are measured by the multivariate linear regression analysis.Finally,partial correlation analysis is performed to identify the relationship between regional ALFF and therapeutic effect.Results:MDD and DA MGPS have interactive effects on the left fusiform,right calcarine,left superior temporal gyrus,bilateral cerebellum posterior lobe,bilateral inferior frontal gyrus and bilateral superior frontal gyrus.Partial correlation analysis reveals that the ALFF of left superior temporal gyrus have a significant negative correlation with 2-week HAMD reductive rate(r=-0.211,P=0.035).Conclusions:The spontaneous activity of left superior temporal gyrus might be a potential biomarker of early antidepressants therapeutic effect underlying the influence of DA pathway genes.Chapter 6.Genetic cumulative effect on spontaneous brain activities in major depressive disorder based on 5-hydroxytryptamine and dopamine pathwayObjectives:This study aims to explore the three-way interactive effect of DA pathway gene,5-HT pathway gene and disease on the spontaneous brain activities in patients with MDD.Methods:95 patients with MDD and 61 HC are recruited.Depression severity is assessed using the HAMD-24,and SHAPS is used to measure the anhedonia symptoms.Both MDD and HC groups are given fMRI scan.The ALFF is calculated to reflect the spontaneous brain activities.The three-way interactive effect of the DA pathway gene,5-HT pathway gene and disease is measured by multivariate linear regression analysis.Partial correlation analysis is performed to identify the relationship between regional ALFF with the severity of MDD and anhedonia.Results:MDD,DA pathway and 5-HT pathway have an interactive effect on the spontaneous activity of right superior frontal gyrus,left cerebellum anterior lobe,right inferior frontal gyrus,right inferior parietal lobe and bilateral precuneus,middle frontal gyrus.The ALFF of left cerebellum anterior lobe has a significant positive correlations with the HAMD-24 score(r=0.219,P=0.037),while the ALFF of right inferior parietal lobe is significantly positively correlated with the SHAPS score(r=0.222,P=0.039).Conclusions:The brain areas that MDD,DA pathway gene and 5-HT pathway gene interactivly effect on are mainly distributed in the fronto-parietal lobes.In addition,the spontaneous activity of cerebellum is also interactivly effected.Moreover,the findings suggest that the left cerebellum anterior lobe may have an important role in the onset of depression,while right inferior parietal lobe may be participated in anhedonia.