ArticleTranslational stroke research2026
Proteome-Wide Mendelian Randomization Identifies Therapeutic Targets for Ischemic Stroke.
Article in Translational stroke research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundIschemic stroke carries substantial residual risk despite acute revascularization and secondary prevention, and small-vessel disease (SVD) lacks specific preventive therapy. Mendelian randomization (MR) using cis-acting protein quantitative trait loci (pQTLs) identifies circulating proteins whose lifelong modulation alters stroke risk.
methodsWe screened 589 conditionally independent cis-pQTLs from the INTERVAL study against four GIGASTROKE outcomes: any ischemic stroke (AIS), large-artery atherosclerosis (LAA), cardioembolic stroke (CES), and SVD. Wald ratio estimates were corrected by Benjamini-Hochberg false discovery rate (FDR) within each outcome, with a pooled cross-outcome correction as a sensitivity analysis. FDR-significant associations underwent colocalization (approximate Bayes factor; H4 > 0.80), replication in the independent deCODE pQTL cohort, cell-type expression validation in a human brain vascular single-nucleus atlas (65,479 nuclei), and phenome-wide safety screening.
resultsTen protein-outcome associations reached FDR < 0.05; nine replicated in deCODE and eight colocalized at H4 > 0.80, with two further pairs (ABO-LAA, cyclin H-CES) in the suggestive range (H4 0.70-0.80). For SVD, higher SPATA20 raised risk (OR 1.47, 95% CI 1.24-1.73, p = 5.3 × 10⁻⁶), and higher KDELC2 lowered risk (OR 0.82, 95% CI 0.74-0.91, p = 2.2 × 10⁻⁴). A protective cyclin H signal for CES passed outcome-wise FDR (q = 0.046) but not the pooled correction (q = 0.059) and is reported as preliminary. ABO, MMP-12, and SWAP70 confirmed earlier reports; SCARA5 failed colocalization and replication and was excluded. Colocalization confirmed the lead liabilities for MMP-12 (atopic dermatitis, two cohorts) and SWAP70 (rheumatoid arthritis) as on-target effects; two further liability associations (allergic asthma, ER-negative breast cancer) did not meet the colocalization threshold and remain hypothesis-generating.
conclusionsProteome-wide MR prioritizes two SVD-associated proteins: SPATA20 (risk-raising; now independently confirmed across screens) and KDELC2 (protective; newly reported). Both require replication on orthogonal proteomic platforms and functional validation before therapeutic development.
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