Genome-wide association study of enlarged perivascular spaces: results from two large population-based cohorts

Enlarged perivascular spaces (PVS) are markers of cerebral small vessel disease (cSVD), implicated in neurovascular and neurodegenerative processes. We conducted a genome-wide association study (GWAS) of quantitative, global PVS volume using brain MRI data from UK Biobank and the Rhineland Study. The meta-analysis (n = 43,050) identified 54 genome-wide significant loci, including 39 novel loci, implicating vascular, inflammatory, cytoskeletal, and metabolic pathways. A parallel GWAS of white matter hyperintensity volume in the same sample showed no significant genetic correlation with PVS, suggesting distinct genetic architectures. Mendelian randomization supported a robust causal effect of systolic and diastolic blood pressure on PVS volume, independent of hypertension diagnosis. We also observed suggestive causal evidence for plasminogen activator inhibitor-1, indicating a potential role for prothrombotic and inflammatory processes. These findings reveal a multifactorial genetic architecture for PVS and underscore vascular dysfunction as a central contributor to cSVD, with implications for prevention and risk stratification.