Shared Genetic Factors Between Alzheimer’s Disease And Ischemic Stroke

Importance: Alzheimer’s disease(AD)is the world’s most leading cause of dementia.Ischemic stroke is the second leading cause of mortality worldwide and another major cause of age-related cognitive decline and dementia,with a high incidence of severe morbidity in surviving victims.These two complicated CNS diseases places a tremendous burden on families and society.Objective: Although converging epidemiological and neuropathological evidence suggests a relationship between Alzheimer’s disease(AD)and ischemic stroke(IS),the nature of this relationship is not well understood.Traditional genome-wide association studies(GWAS)based on single SNP-based analysis failed to uncover shared genetic factors between AD and overall IS,which motivates us to initiate this study into systematically investigating whether shared genetic factors contributed to their phenotypic association.Participants and methods: Taking advantage of summary data from two large published genome-wide association studies on AD(17,008 cases,37,154 controls from International Genomics of Alzheimer’s Project stage 1)and IS(10,307 cases,19,326 controls from the METASTROKE collaboration),we explored shared genetic basis from the perspective of SNPs,genes,gene expression and functional pathways jointly associated with AD and IS.Results: We found 4 independent loci jointly associated with AD and IS with genome-wide statistical significance,including rs115499691 in HLA region,rs7938634 in PICALM locus,rs73154208 in EPHA1 locus,and rs632185 in MS4 A locus.All these loci demonstrated the same direction of allelic effect between AD and all IS.Using gene-based association test,we deciphered 10 shared genes associated with both AD and IS with nominal significance(P < 0.05)in each disease,among which 3 genes achieved gene-wide significance after multiple test correction(ZYX,EPHA1 and EFTUD1)with the other 7 genes(MS4A4A,YDJC,UBE2L3,PABPC1,RRN3P1,FAM154 B,and TREM2)at or near the suggestive significance(P < 1.00E-4).Of these,8(ZYX,EPHA1,EFTUD1,MS4A4 A,UBE2L3,YDJC,PABPC1 and TREM2)were further validated following subsequent analysis of AD and IS case-control expression datasets.In the subsequent pathway analysis,we identified 6 KEGG pathways,179 GO pathways(56 biological processes,95 cellular components,and 28 molecular functions).Of these,two KEGG pathways(hsa04650 Natural killer cell mediated cytotoxicity and hsa04620 Toll-like receptor signaling pathway)involving the innate arms of the immune system,contribute to the associated pathways between AD and IS.Conclusion: Our findings deciphered the genetic correlation between AD and IS and highlighted immune system process responsible for the development and progression of these two complicated CNS diseases.The results may have novel implications for future mechanistic studies and guide future research directions regarding AD and IS.