Identification Of Shared Genes Between Ischemic Stroke And Parkinson's Disease

OBJECTIVE: Ischemic stroke and Parkinson's disease are two major central nervous system diseases that often threaten the elderly.Numerous genetic and clinical evidence has been reported for ischemic stroke and Parkinson's disease.Through a multi-step systemic genome-wide association studies analysis,we aim to explore the shared genetic mechanism of the two diseases,which may provide new insight for developing novel therapies of the two diseases.METHODS: We utilized summary genome-wide association studies(GWAS)data of ischemic stroke(IS)from METASTROKE(included 9,541,572 SNPs from 10,307 patients and 19,326 controls)and summary GWAS data of Parkinson's disease(PD)(included 2,525,704 SNPs from 4,238 patients and 4,239 controls)to conduct a gene-based test to identify the respective susceptibility genes for both diseases.Subsequently a simple meta-analysis was conducted on the p-values of the same susceptible genes of two diseases,followed by the Bonferroni correction.Ultimately,we identified shared susceptibility genes of the two diseases.Utilizing the public results from microarray experiments,we explored whether there is a difference in the expression of shared susceptibility genes between IS and PD in GEO(Gene Expression Omnibus)datasets.We further verified whether the shared susceptibility genes of the two diseases have differential transcriptional expression in different tissues(whole blood,peripheral blood,and brain)of the two diseases through a transcriptome-wide association study(TWAS).RESULTS: A total of nine genes(NUDT14,PARP3,GPX7,ZCCHC10,MEX3 A,DENND2A,CRNN,RGS9 BP and LBH)reached statistical significance on gene levels through a gene-based test.Taking advantage of microarray experiments in GEO datasets,we identified that LBH showed differential expression level in the blood tissues of IS samples(GSE16561)and PD samples(GSE22491)compared to control subjects;and in brain tissue,PARP3 and GPX7 were expressed differentially in IS samples(GSE38037)and PD samples(GSE20295)comparing with controls.Likewise,other genes were differentially expressed in different samples of IS and PD,except for MEX3 A and RGS9 BP.Through the transcriptome-wide association study,NUDT14 and DENND2 A were shown to be significantly associated with the two diseases in the brain tissues;LBH was detected significantly altered transcript levels of the two diseases in peripheral blood tissues;and the expression level of GPX7 in IS patients was also reached the statistical significance.Conclusions: Our study revealed that IS and PD do have genetic links at the genetic level: shared genes,through the gene-based test and two expression-based validation methods,utilizing IS and PD GWAS datasets.What's more,these shared genes are functionally differentially expressed in IS and PD patients compared to neurologically healthy control participants in different tissues.In particular,both GPX7 and LBH reach significant threshold through two gene expression analyses.This finding provides new evidence for us to reveal the mechanistical links between IS and PD,and would be a valuable guidance to study the genetic basis of the two diseases and develop new therapies in the future.