Genome-Wide Data Integration Analysis Of Psychiatric Disorders

Over the past decade,genome-wide association analysis becomes a powerful tool to explore the genetic bases of common diseases.However,it is hard to understand the mechanism underlying between the loci identified by genome-wide association studies(GWASs)and diseases due to the SNP either belong to the non-coding or within the linkage disequilibrium(LD)region.Whereas,several approaches have been developed to explore the GWAS-finding by integrating GWAS data with multi-omics data.The recent increase in the psychiatric GWASs provides the baseline to explore the biological mechanism and molecular pathways associated with the psychiatric disease.Several studies have explored the GWASs finding of a psychiatric disorder such as for schizophrenia(SZ)and bipolar disorder(BPD).Whereas,the pathophysiology of the ADHD and the causal relationship of the psychiatric disorders with other traits such as diet-intake/lifestyle factors and vitamin supplementations are still not revealed.In this thesis,we explored the causal genes and gene expression analysis of ADHD by using recent genome-wide meta-analysis data.In addition,we explored the causal relationship of diet-intake/lifestyle with psychiatric disorders as well as the causal effect of SZ on vitamin supplementation.Moreover,the functional annotation and data integration analysis was carried out to study the biological and molecular mechanism underlying the SZ-associated SNPs(including LD proxy SNPs).Four studies were conducted based on the aim of this thesis.Study 1:Objective: Recent genome-wide meta-analysis identified 12 independent loci for Attention-deficit hyperactivity disorder(ADHD).However,the expression and pathways of causal genes associated with ADHD are still vague.Methods: We integrated GWAS,e QTL,and genes expression data to find the causal genes,genes expression,and genes prioritization in the different brain tissues and whole blood cells.Results: Overall,47 genes were prioritized;the most promising genes were LSG1,HYAL3,PIDD,PNPLA2,BLOC1S2,PLK1S1,CALN1,KAT2 B,CTNNB1 and WDR11.Whereas,the CALN1,KAT2 B,and WDR11 were previously associated with schizophrenia(SZ),bipolar(BP)and drug abuse.Gene ontology analysis shows that the glutamate receptor signaling pathway(P = 8.009E-07,with false discovery rate(FDR)< 5%),GRIK5 subnetwork(P = 2.887E-06,FDR < 5%),abnormal gait(P = 3.657E-06,FDR < 5%),REACTOME_SIGNALING_BY_ERBB2(P = 5.161E-06,FDR < 5%),and abnormal nervous system physiology(P = 5.239E-06,FDR < 5%)were associated with ADHD.Furthermore,these causal genes were highly expressed in Fetal Astrocytes,Neurons,and Microglia/Macrophage.Conclusion: This study illustrates the comprehensive GWAS integrative approach of ADHD.However,further genetic and functional studies are required to validate the role of these genes in the aetiology of ADHD,which should provide novel insights into the understanding of this disease.Study 2:Objective: SZ is a multifactorial neurobiological background and a complex genetic disorder that affects approximately 1% of people around the world.SZ GWASs identified more than 100 loci.These SNPs mostly lies in the non-coding region,which makes it hard to determine the specific functional association.In this study,we conduct a multi-approach analysis to find functional annotation of the SZ-associated SNPs,including proxy SNPs.Methods: SZ-GWAS associated SNPs were retrieved from recently published Li et al.(2017)SZ-GWAS data.Whereas,1000 genomes data was used to fetch the proxy SNPs for SZassociated SNPs.First,these SNPs were functionally prioritized via Regulome DB and depict.The prioritized SNPs were then functionally annotated via SZDB,DAVID,Ri Net and STRING server.Results: overall,335 proxy SNPs were prioritized via Regulome DB.Whereas SZDB analysis showed that 94 proxy SNPs(206 association)were found in the m QTL(DNA methylation quantitative trait loci P value > 5e08)that were associated with 40 genes and the total number of total methylation sites were 38,while 10 proxy SNPs were associated with 13 e QTL gene expression.Similarly,6 functional SNPs were associated with mi RNA binding 5'utr region that affects the gene expression of DRG2,LSM1,UBE2Q2P1,APH1 A,and CISD2.Gene ontology(GO)analysis shows that these proxy-associated were highly enriched in the SZ.Moreover,the prioritized proxy SNPs were involved in the cell adhesion and ion binding process.Conclusion: Current study analysis demonstrate an in-depth view of the SZ associated proxy SNPs.We found that these proxy SNPs involved in the SZ-associated gene expression,mi RNA-genes and mi RNA-molecules interaction.Further exploration of predicted genes and mi RNA need to understand the role of these genes and mi RNAs in the prevalence of SZ.Study 3:Objective: Observational studies have proven that unhealthy life is associated with psychiatric disorders.However,the causal relation of unhealthy life,e.g.dietary-intake and lifestyle factors,remains vague.We conducted the Mendelian Randomization(MR)analysis to explore the causal association of unhealthy life with psychiatric diseases in this study.Methods: Two-sample MR approach was used to assess the causal relationship of daily macronutrients intake,smoking,sleep duration and sleep disturbance with psychiatric disorders.Sensitivity analysis was conducted to assess precise results by eliminating pleiotropy and confounder bias.Results: We did not find causal relation of unhealthy-lifestyle with SZ i.e.(carbohydrates-intake beta =-0.068,SE = 0.111,P-value = 0.541,higher protein-intake,beta =-0.039,SE = 0.111,P-value = 0.727,smoking initiation,beta = 0.019,SE = 0.011,P-value = 0.083 and cigarette per day decrease,beta=-0.001,SE = 0.02,P-value = 0.962,while unusual sleep,beta = 0.001,SE = 0.003,P-value = 0.704),similarly our analysis does not support causal relation of unhealthy-lifestyle with MDD,cognitive function and depressive symptoms.However dietary-intake was found to be a causal risk for BPD(dietary macronutrient percent decrease-intake beta=-0.639,SE= 0.2132,P-value= 0.0027,and dietary macronutrient % decrease fat-intake beta =-0.4292,SE= 0.115,P-value = 0.00018).Conclusion: Our results support that unhealthy diet-intake are the causal risk for BPD.These piece of evidence provide the further logic that the proper monitoring of diet-intake needs in individuals at risk of psychiatric disorders.Study 4:Objective: Observational studies have reported the malnutrition and deficiency of essential vitamins in SZ patients,which may lead to severe metabolic syndromes and decrease anti-psychiatry drug outcomes.However,it is still unclear whether SZ has causal role of malnutrition and abnormal vitamin supplementation.Methods: We conduct the Two-sample Mendelian randomization analysis to evaluate the causal effect of SZ on vitamin supplementation followed by sensitivity analysis to obtain accurate finding and eliminate confounder bias.Results: We found the causal role of SZ with vitamin A,B,C and E i.e.SZ/vitamin A beta = 0.003(0.002,0.004),SE = 0.001,P-value = 0,heterogeneity P-value = 0.8481,SZ/vitamin B beta = 0.004(0.002,0.005),SE = 0.001,P-value = 0,heterogeneity Pvalue = 0.8002,SZ/vitamin C beta = 0.004(0.002,0.006),SE = 0.001,P-value = 0,heterogeneity P-value = 0.6759,SZ/vitamin E beta = 0.003(0.002,0.005),SE = 0.001,P-value = 0,heterogeneity P-value = 0.4321 respectively.These results suggest that SZ is a causal risk for vitamins deficiency and abnormal vitamin supplementation.Conclusion: These shreds of evidence provide the logical reason for proper monitoring of vitamins levels and supplementation in schizophrenia patients,which may influence the therapeutic effects of antipsychotic drugs treatments.