Genetic Association Study Between Multiple Sclerosis And Ischemic Stroke

Background and Objective: Multiple sclerosis(MS)and ischemic stroke(IS)are two neurological diseases with high rates of disability and associated with huge personal,family,and socioeconomics burden.MS and IS have the complex etiology and pathogenesis,diverse symptomatology and limited benefits of therapies.All of these make them thorny in the field of medical research.Up to now,the association between MS and IS has been understood because clinical studies not only revealed an increased prevalence of IS in MS patients compared with controls,but also administered immunomodulatory drugs,which are FDA-approved agents for MS,in IS clinical translation experiments.However,the genetic association between the two diseases remains to be explored.This study focused on the association of genetic between MS and IS.We utilized and analyzed the GWAS datasets to figure out the associated genes and biological pathways.The discoveries can help people excavate the potential pathogenic mechanisms.They also provide great genetic basis for the understanding and prevention of disease risk factors and the discovery of potential therapy targets.Participants and methods: We selected MS-GWAS data and IS-GWAS data and identified the overlapped genes and the shared biological pathways between MS and IS.First,we applied the PLINK software to conduct the gene-based association analysis with SNPs in MS and IS GWAS data respectively and identified the risk gene sets of per-disease with P < 0.05.Then we combined the P value of initial overlapped genes in per-disease with Fisher's method in order to figure out the overlapped risk genes after multiple test correction.Subsequently,we selected the significant overlapped risk genes after multiple test correction and analyzed the differential expression of them in the MS-control and IS-control samples via GEO database from the NCBI.Finally,we executed enrichment analysis and functional annotation for risk gene set of per-disease respectively by using the Web Gestalt and identified the shared biological pathways between two diseases.Results:In gene-based association analysis,we found 23 significant overlapped risk genes between MS and IS(ARFRP1,ATOX1,C12orf30,CLEC2 D,CLECL1,LIME1,LTA,MICB,MYO19,NFKBIL1,NUDT14,PPP1R10,RING1,RPS13,RTEL1,SH2B3,SLC26A10,SLC44A2,UBE2 B,WARS,ZFP36L1,ZNF746 and ZNHIT3).Gene differential expression analysis identified that seven of 23 shared risk genes(CLEC2D,MYO19,PPP1R10,UBE2 B,WARS,ZFP36L1 and ZNF746)had significant differential expression in the MS-control and IS-control samples.And the expression of ZFP36L1 in peripheral blood mononuclear cells of MS was 2.20-fold higher than that of control;the expression of UBE2 B in peripheral blood cells in cardioembolic stroke(a major subtype of IS)was 2.07-fold higher than that of control.In parhway-based analysis,we obtained twelve significant KEGG shared pathways,two significant PANTHER shared pathways,five significant Wiki Pathways shared pathways and 25 significant Reactome shared pathways between MS and IS.Besides,we found that MS and IS shared 121 significant GO annotations,including 56 biological processes annotations,43 cellular components annotations and 22 molecular functions annotations.After further processing and analysis,we identified 19 significant representative GO annotations,including twelve biological processes annotations,three cellular components annotations and four molecular functions annotations.Conclusion: Based on the levels of gene and biological pathway,this study researched the genetic association between MS and IS respectively.And this study uncovered the common genetic basis between MS and IS,suggesting that the genetic changes of immune and nervous system may be related to the occurrence and development of MS and IS.In conclusion,this study provides strong genetic evidence for the association between MS and IS and gives new clues and ideas for the further researches on the common molecular mechanism of MS and IS.