Modifiable Pathways in Cerebral Small Vessel Disease: A Two-Sample Mendelian Randomization Analysis

Abstract

Objective: We investigated the causality between modifiable risk factors and the risk of two cerebral small vessel disease phenotypes: small vessel stroke (SVS) and white matter hyperintensity (WMH). Methods: Genetic instruments for multiple risk factors were obtained from previous genome-wide association studies. We applied two-sample Mendelian randomization methods to investigate their causal relationship with SVS and WMH from the MEGASTROKE genome-wide association study and the UK Biobank neuroimaging dataset. Results: Genetic analysis predicted that smoking initiation (OR 1.39, 95% CI 1.22-1.57, p=2.31×10-7), systolic blood pressure (OR 1.05, 95% CI 1.03-1.07, p=1.82×10-7), pulse pressure (OR 1.06, 95% CI 1.03-1.10, p=2.14×10-4), type 2 diabetes mellitus (OR 1.20, 95% CI 1.13-1.27, p=1.08×10-9), and hemoglobin A1c (OR 1.40, 95% CI 1.20-1.62, p=1.28×10-5) were associated with an increased risk of SVS; infant head circumference (OR 0.59, 95% CI 0.46-0.75, p=1.56×10-5), high-density lipoprotein cholesterol (OR 0.84, 95% CI 0.77-0.93, p=3.75×10-4) and folate level (OR 0.50, 95% CI 0.35-0.71, p=1.36×10-4) were associated with a decreased risk of SVS; and smoking initiation (β 0.13, 95% CI 0.06-0.19, p=7.01×10-5) was associated with a decreased risk of WMH. Suggestive associations were found between glycemic traits, dietary carbohydrates and SVS and between infant head circumference, estimated glomerular filtration rate (eGFR), trimethylamine-n-oxide (TMAO) and WMH. Interpretations: Compared with previous MR analyses, our study additionally revealed that infant head circumference is causally associated with SVS and that smoking is causally associated with WMH. Several risk factors are suggestively associated with cerebral small vessel disease. Funding Information: This study was supported by Beijing Municipal Science and Technology Commission (grant numbers D141100000114005). Declaration of Interests: None.