Improved Detection Of Common Variants In Ischemic Stroke And Dyslipidemia Using A Pleiotropy CFDR Method

Genome-wide association studies(GWASs)have been performed extensively in different populations to identify single nucleotide polymorphisms(SNPs)associated with complex diseases or traits.However,up to now,the SNPs identified of ischemic stroke(IS)and Dyslipidemia(DL)fail to explain a large proportion of the heritability.Although DL is a major risk factor for IS and two phenotypes share both genetic factors,the genetic intercommunity(genetic pleiotropy)between them remain largely unknown.To identify novel loci associated with IS and DL,a genetic-pleiotropy-informed conditional false discovery rate(cFDR)method was applied on two summary statistics of IS and DL from existing GWASs.ObjectiveTo recognize novel SNPs associated with IS and DL(including total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C),triglyceride(TG)and high-density lipoprotein cholesterol(HDL-C)),especially novel pleiotropic loci.MethodscFDR method was applied on summary statistics of IS and DL(HDL-C,LDL-C,TC and TG)from existing GWASs.The SNPs were identified for IS and DL by calculating the cFDR and conjunction cFDR values.Stratified Q-Q and fold enrichment plots were applied to assess the pleiotropic enrichment between both traits.Conditional manhattan plots were conducted to illustrate the SNPs’ genomic locations.Function term enrichment analysis and pathway analysis of individual traits related gene were performed in the DAVID database.ResultsStratified Q-Q and fold enrichment plots showed a high pleiotropic enrichment of SNPs associated with two traits.Adopting a cFDR significance level of 0.05,14 ISassociated SNPs(10 variants being novel)and 660 DL(HDL-C,LDL-C,TC and TG)related-SNPs(324 variants being novel)were identified,10 of which were pleiotropic SNPs(7 variants being novel)for both diseases.Among the 12 genes these 10 SNPs were annotated to,9 genes were newly detected compared to previous GWASs.Function term enrichment analysis and pathway analysis showed that most genes play a role in lipoprotein metabolic process,lipid homeostasis,carbohydrate metabolic process and cholesterol homeostasis.ConclusionsIn this study,stratified Q-Q plots showed a high pleiotropic enrichment,which confirmed that IS was associated with HDL-C,LDL-C,TC and TG.The cFDR method successfully identified 10 and 324 novel SNPs related to IS and DL,respectively.These findings were partially validated by GO terms and KEGG analysis,which indicating the high feasibility of this method.The 12 pleiotropic genes may provide novel insights into the unknown shared biological mechanism between IS and DL,and have significant implications for the joint prediction of the two diseases.