A large-scale genomic analysis of white matter hyperintensities (WMH) — the brain's most common MRI marker of small vessel disease — constructed a validated global polygenic risk score (PRS) from a 46,944-person GWAS and tested it across four independent cohorts totaling over 370,000 individuals. The global WMH-PRS predicted lesion burden from young adults (age ~22, ΔR²=+0.5%) through elderly memory-clinic patients (ΔR²=+3.3%), and in UK Biobank associated with incident ischemic stroke (HR=1.061), intracerebral hemorrhage (HR=1.083), and vascular dementia (HR=1.168). Among 3,794 pathway-specific PRS tested, 127 showed consistent enrichment clustering into ten biological domains, with lipid metabolism, ciliogenesis, sphingolipid pathways, and signal transduction emerging as cross-lifespan contributors.
The sphingolipid and ciliogenesis findings are particularly striking — these pathways have received limited attention in cerebrovascular research despite emerging evidence linking sphingolipid dysregulation to endothelial dysfunction and neuroinflammation. The cross-age validation from young adults to memory-clinic patients suggests WMH genetic architecture operates continuously rather than only in late-life disease contexts, with implications for early intervention windows. Practically, a PRS explaining ~3-4% of WMH variance is modest but meaningful at population scale for stratifying stroke and dementia risk. Critical limitations include European-ancestry restriction limiting generalizability, the observational design precluding direct causal pathway inference, and the MRI cohort's age skew. As a preprint not yet peer-reviewed, these pathway enrichment findings — derived from thousands of statistical tests — require independent replication and scrutiny of multiple-comparison controls before clinical translation.