Cell-type-stratified Mendelian randomization implicates neuronal and neurovascular expression programs in the causal effect of coronary artery disease on stroke: analysis code, result tables, and figures

Version 4 (2026-09-30): Archived manuscript and figures synchronized with the revised version submitted to Stroke (STROKE/2026/058460). The statistical power statement was re-derived from the standard errors implied by the reported confidence intervals (the earlier power figure, computed from an assumed instrument variance, was not reproducible from the reported intervals and has been replaced by the empirically calibrated value, 84% at α = 0.0125); minimum detectable odds ratios are now reported under both a model-based and an empirically calibrated framework. A formal between-stratum heterogeneity test was added (ischemic stroke Q = 2.86, df = 3, P = 0.41; any stroke Q = 4.00, P = 0.26), and cell-type-stratified results are described as exploratory effect-size patterns rather than evidence of specificity. Figure 1 was re-rendered (single page; the superseded power statement replaced by the empirically calibrated power; between-stratum Q added to the key-estimates panel) and is now archived at ≥1200 dpi; Figure 2 label spelling follows AMA style ("Alzheimer disease"). Files from earlier journal-specific drafts were removed so that the archive matches the version submitted to Stroke; the superseded files remain available in version 3 of this record. No estimate, confidence interval, or conclusion changed relative to version 3 except the power and minimum-detectable-effect statements above, which are corrections.Version 3 (2026-09-24): Header of the supplementary materials corrected — manuscript title aligned with the current version and the author list updated to include Xue Zhang. No changes to data, analyses, or results.Version 2 (2026-09-23): Manuscript text updated (abstract condensed); reference DOIs completed; STROBE-MR checklist item 19 updated to cite this record; the manuscript now cites the concept DOI 10.5281/zenodo.22848330 so that the reference always resolves to the latest version. Figure 2 Alzheimer disease label corrected to the proxy-inclusive sample size (111,326 cases / 677,663 controls); Figure 1 re-rendered with American spelling; Supplementary Materials now cite this DOI instead of a local file path. No numerical result changed from version 1.Code, result tables, and figures for a two-sample Mendelian randomization (MR) study in which instruments for coronary artery disease (CAD) were filtered by colocalization (coloc.abf, PPH4 ≥ 0.8) with brain cell-type-specific cis-eQTLs from single-nucleus transcriptomics of human cortex (Bryois et al., Nature Genetics 2022). Of 274 CAD lead loci, 32 colocalized with brain-cell eQTLs, yielding 32 cell-annotated instruments (excitatory neurons 12, pericytes 7 after palindrome exclusion, oligodendrocytes 5, astrocytes 3, microglia 2, inhibitory neurons 1, OPC 1) explaining 3.4–5.6% of CAD liability on the liability scale.Random-effects inverse-variance weighted estimates (with weighted median, MR-Egger, leave-one-out, Cochran's Q and I², MR-PRESSO-analog global permutation, outlier correction, and MR-Steiger sensitivity analyses) are provided for ischemic stroke (OR 1.335, 95% CI 1.189–1.498, p = 1.0e-6), any stroke (OR 1.309, p = 8.5e-7), Alzheimer disease (proxy-inclusive, and a clinically diagnosed replication arm), and major depression (null negative control). Cell-type-stratified estimates are largest for neuronal and neurovascular-unit (pericyte) expression programs.Contents: full analysis pipeline (R 4.6 / Python 3.13), all derived result tables (instruments, colocalization posteriors, harmonized exposure–outcome pairs, primary and stratified MR, leave-one-out, Steiger), publication figures (SVG/PDF vector plus raster PNG), the manuscript, supplementary tables S1–S8, and the completed STROBE-MR checklist. Raw GWAS summary statistics are not redistributed; all sources are public (GWAS Catalog accessions GCST90132315, GCST006908, GCST006906, GCST90027158, GCST007511, GCST005839; eQTL record 10.5281/zenodo.7276971) and every number needed to reproduce the tables and figures is included.