A latent genetic factor underlies multiple component phenotypes of cerebral small vessel disease

BACKGROUND: Cerebral small vessel disease (cSVD) encompasses white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), intracerebral hemorrhage (ICH), small vessel stroke (SVS), and cognitive impairment-phenotypes that frequently co-occur yet have been studied as independent genetic endpoints. Whether a shared genetic architecture underlies these co-occurring cSVD-related phenotypes remains unclear. METHODS: We applied Genomic SEM to GWAS summary statistics from six phenotypes (WMH, PVS, ICH, SVS, cognitive performance, systolic blood pressure), followed by multivariate association scanning, Bayesian fine-mapping (SuSiE/FINEMAP), gene-level (MAGMA) and transcriptome-wide (sCCA-TWAS/FOCUS) analyses, pathway enrichment, cell-type specificity (CELLECT) and spatial developmental mapping (gsMap). RESULTS: A common-factor model fit the data well (CFI = 1.00, SRMR = 0.061). The multivariate scan identified 1,423 genome-wide significant SNPs, resolving into 20 independent lead SNPs mapped to 14 distinct genomic loci, of which 2 were not detected at genome-wide significance in any constituent single-trait GWAS. Fine-mapping prioritized three high-confidence causal variants at EFEMP1, ICOSLG, and AC098824.6. Gene-level and transcriptome-wide analyses converged on effector genes at 17q25.1 (TRIM47/TRIM65), 10q24.33 (SH3PXD2A), and 2q33.1 (NBEAL1). MAGMA additionally identified APOE at 19q13.32. Pathway analysis highlighted epigenetic dysregulation, cellular senescence, and amyloid fiber formation. CELLECT identified vascular endothelial cells and pericytes as enriched cell types. gsMap revealed developmental enrichment in lung, kidney, and meninges exceeding brain tissue. CONCLUSIONS: These findings delineate a coherent latent genetic structure linking multiple cSVD-related phenotypes, rooted in vascular wall cell biology, epigenetic regulation, and cellular senescence, with developmental origins spanning multiple organ microvascular beds.