Cardiovascular Risk Factors and MRI Markers of Cerebral Small Vessel Disease: A Mendelian Randomization Study

Objective- Cardiovascular risk factors have been implicated in the etiology of Cerebral Small Vessel Disease (CSVD), however whether the associations are causal remains unclear in part due to the susceptibility of observational studies to reverse causation and confounding. Here we use Mendelian randomization (MR) to determine which cardiovascular risk factors are likely to be involved in the etiology of CSVD. Methods- We used data from large scale genome-wide association studies (GWAS) of European ancestry to identify genetic proxies for blood pressure, blood lipids, body mass index (BMI), type-II diabetes, smoking initiation, cigarettes per day and alcohol consumption. MR was performed to assess their association with three neuroimaging features which are altered in CSVD (white matter hyperintensities (WMH), fractional anisotropy (FA) and mean diffusivity (MD)) using genetic summary data from UK Biobank (N=31,855). Our primary analysis used inverse-weighted median (IVW) MR, with validation using weighted median, MR-Egger and a pleiotropy-minimizing approach. Finally, multivariable MR was performed to study the effects of multiple risk factors jointly. Results- MR analysis showed consistent associations across all methods for higher genetically proxied systolic and diastolic blood pressure with WMH, FA, and MD; and for higher genetically proxied BMI with WMH. There was weaker evidence for associations between total cholesterol, LDL, smoking initiation, pulse pressure and type-II diabetes liability and at least one CSVD imaging feature, but these associations were not reproducible across all validation methods used. Multivariable MR analysis for blood pressure traits found that the effect was primarily through genetically proxied diastolic blood pressure across all CSVD traits. Conclusion- Genetic predisposition to higher blood pressure, primarily diastolic blood pressure, and higher BMI is associated with a higher burden of CSVD, suggesting a causal role. Improved management and treatment of these risk factors could reduce the burden of CSVD.