Identification of causal plasma metabolite biomarkers for ischemic stroke using Mendelian randomization and mediation analysis

Figures

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  Fig. 1. Overall study design. IS ischemic stroke, MR Mendelian randomization, SNPs single nucleotide polymorphisms, GWAS genome-wide association studies, CLSA Canadian Longitudinal Study on Aging, BMI body mass index, LDL low-density lipoprotein, HDL high-density lipoprotein, non-HDL non-high-density lipoprotein, SBP systolic blood pressure, DBP diastolic blood pressure, T2D type 2 diabetes, CHD coronary heart disease, MR-PRESSO MR pleiotropy residual sum and outlier, FDR false discovery rate, OR odds ratio, IVs instrumental variables, PheMR phenome-wide MR.

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  Fig. 2. Circular clustering heatmap of the causal relationship between 1,400 metabolites and IS based on five MR methods. MR Mendelian randomization, IVW inverse variance weighted. GWAS data for 1400 metabolites from the CLSA cohort (Supplementary Table S1). IS GWAS data from the IEU databases (ebi-a-GCST005843).

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  Fig. 3. Effects of 19 potential causal metabolites on IS outcomes. Primary MR estimates were calculated using the inverse-variance weighted method under multiplicative random effects. Using MR-PRESSO, we identified 19 metabolites that were causally associated with IS.

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  Fig. 4. Causal effects of five risk factors on IS outcomes. MR analyses of the effect of risk factors on stroke outcomes. GWAS data of IS risk factors from the IEU databases. Primary MR estimates were calculated using the inverse-variance weighted method under multiplicative random effects. BMI, HDL, SBP, DBP, and T2D demonstrated positive correlations with IS, identifying them as risk factors. BMI body mass index, HDL high-density lipoprotein, SBP systolic blood pressure, DBP diastolic blood pressure, T2D type 2 diabetes.

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  Fig. 5. Among the nineteen IS-associated metabolites, four were identified as being associated with one of the IS risk factors. MR analyses of the effect of metabolites on IS and IS risk factors. The leftmost column shows 19 IS-associated metabolites. X-24,951 was identified as being associated with BMI. 1-stearoyl-GPG (18:0) and 1-oleoyl-2-linoleoyl-GPE (18:1/18:2) were identified as being associated with DBP. Octadecadienedioate (C18:2-DC) was identified as being associated with coffee intake. *Indicates that the causal association is significant, which passed p < 0.05, false discovery rate (FDR) < 0.2, consistent OR direction across five MR methods, and pleiotropy > 0.05. BMI body mass index, LDL low-density lipoprotein, HDL high-density lipoprotein, non-HDL non-high-density lipoprotein, SBP systolic blood pressure, DBP diastolic blood pressure, T2D type 2 diabetes, CHD coronary heart disease.

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  Fig. 6. Mediation effects of metabolites on IS via risk factors. Mediation analyses to quantify the effects of four metabolites on IS outcomes via risk factors. (a) 1-stearoyl-GPG (18:0) levels effect on IS mediated by DBP. (b) 1-oleoyl-2-linoleoyl-GPE (18:1/18:2) effect on IS mediated by DBP. (c) Octadecadienedioate (C18:2-DC) effect on IS mediated by coffee intake. (d) X-24,951 effect on IS mediated by BMI. βEM: effects of exposure on mediator, βMO: effects of mediator on outcome, βEO: effects of exposure on outcome. IVs instrumental variables.