Association Between Cardiovascular Polygenic Risk and White Matter Hyperintensities: An Observational Study From the...

White matter hyperintensities (WMH), a marker of cerebral small vessel disease, are associated with cardiovascular risk factors and disease. However, the extent to which these associations are driven by shared genetic architecture remains unclear.

Using data from 44 996 UK Biobank participants, we evaluated associations between WMH subtypes (total WMH, deep WMH, and periventricular WMH) and polygenic risk scores (PRSs) for 35 diseases and traits. Associations were tested using χ² and multivariable linear regression models. Cox models assessed whether WMH burden modified cardiovascular risk across genetic risk strata. Multiomics data were examined to identify biomarkers jointly associated with WMH and disease-specific PRSs.

Higher WMH burden was associated with increased PRSs for cardiovascular disease (CVD), hypertension, ischemic stroke, and blood pressure, with the strongest associations observed for total WMH. WMH burden was prospectively associated with higher CVD incidence among individuals with high CVD PRS (hazard ratio, 2.54 [95% CI, 1.44-4.45]), but not among those with low PRS. For hypertension, WMH burden was associated with increased risk in both PRS strata, with stronger associations in individuals with high hypertension PRS, indicating additive contributions of genetic susceptibility and WMH burden. Lifestyle influences varied by genetic background: longer sleep duration and lower body mass index were protective only with low CVD PRS. Multiomics analyses identified 46 circulating biomarkers jointly associated with WMH and CVD PRSs, predominantly related to lipid metabolism.

The association between WMH burden and cardiovascular-related disease risk is influenced by genetic background, supporting precision risk stratification and prevention in clinical practice.