Pathway-specific polygenic risk scores reveal underlying mechanisms of cerebral small vessel disease

Abstract

White matter hyperintensities (WMH), a key MRI-marker of cerebral small vessel disease (cSVD), are common in older adults and associated with an increased risk of stroke and dementia. The latest WMH genome-wide association study (GWAS) identified 27 loci involving genes enriched for extracellular matrix, myelination, and membrane transport. Genetically predicted WMH correlates with white matter microstructural alterations in young adults and shows causal effects on stroke and dementia. However, biological pathways underlying WMH and their contribution to clinical outcomes remain unclear, and validated polygenic risk scores (PRS) for WMH are lacking. We applied global and pathway-specific PRS (ps-PRS) to generate robust WMH-PRS and identify biological pathways contributing to WMH across the lifespan. We leveraged the largest European-ancestry WMH-GWAS (N=46,944) and data from 15,320 UK Biobank participants with MRI (UKB-MRI) (mean age=67 (7.7) years) to optimize a WMH global-PRS and construct 3,794 ps-PRS based on canonical pathways from the Molecular Signatures Database (v2023.2). The best WMH global-PRS in UKB-MRI (P=1.78 x e-193; delta-R-squared=+4.1%) predicted WMH in independent cohorts: young adults (i-Share, N=1,578, age=22(2.3); P=0.0024; delta-R-squared=+0.5%), older community-dwellers (Three City-Dijon, N=1,443, age=73 (4.1); P=1.38xe-9; delta-R-squared=+2.2%), and memory-clinic patients (Memento, N=1,831, age=71 (8.5); P=1.11xe-19; delta-R-squared=+3.3%). In the UK Biobank (N up to 355,180), WMH global-PRS was associated with incident stroke (HR=1.06 [1.038, 1.082], P=2.6xe-8), including both ischemic stroke (HR=1.061[1.037, 1.086], P=1.6xe-8) and intracerebral hemorrhage (HR=1.083[1.026, 1.143], P=0.004). Higher global-PRS was also associated with incident all-cause dementia (HR=1.051 [1.030, 1.080], P=1xe-5) and its vascular or mixed dementia sub-type (HR=1.168[1.103, 1.237], P=1.1xe-7), but showed no association with Alzheimer's disease. Permutation-based pathway enrichment, performed in UKB-MRI, identified 127 ps-PRS consistently enriched for WMH and clustering into ten biological domains. Of these, 61 ps-PRS (six clusters and 55 individual pathways) were enriched in at least one follow-up cohort: 14 in older community-persons, 17 in young adults, and 37 in memory-clinic patients. Secondary analyses highlighted four ps-PRS involved in lipid metabolism, ciliogenesis, and signal transduction enriched in both young and older adults and associated with stroke and dementia. In the memory-clinic some ps-PRS, notably involved in sphingolipid metabolism, were also associated with dementia. Seven ps-PRS, mostly lipid-related, showed evidence of modulation by hypertension. In summary, we generated a validated WMH global-PRS showing robust association with cSVD clinical complications and introduce a multi-cohort WMH ps-PRS framework that reveals candidate biological pathways with differential associations across the lifespan and clinical outcomes. These findings may inform precision prevention and drug development for cSVD.