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Abstract
Background and Objectives 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 of European ancestry to identify genetic proxies for blood pressure, blood lipids, body mass index (BMI), type 2 diabetes, smoking initiation, cigarettes per day, and alcohol consumption. MR was performed to assess their association with 3 neuroimaging features that are altered in CSVD (white matter hyperintensities [WMH], fractional anisotropy [FA], and mean diffusivity [MD]) using genetic summary data from the UK Biobank (N = 31,855). Our primary analysis used inverse-weighted median 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 pressures with WMH, FA, and MD and for higher genetically proxied BMI with WMH. There was weaker evidence for associations between total cholesterol, low-density lipoprotein, smoking initiation, pulse pressure, and type 2 diabetes liability and at least 1 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.
Discussion Genetic predisposition to higher blood pressure, primarily diastolic blood pressure, and to 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.
Glossary
- BMI=
- body mass index;
- CSVD=
- cerebral small vessel disease;
- DBP=
- diastolic blood pressure;
- DTI=
- diffusion tensor imaging;
- FA=
- fractional anisotropy;
- GWAS=
- genome-wide association studies;
- HbA1c=
- hemoglobin A1c;
- HDL=
- high-density lipoprotein;
- ICBP=
- International Consortium of Blood Pressure;
- IVW=
- inverse-variance weighted;
- LDL=
- low-density lipoprotein;
- MD=
- mean diffusivity;
- MR=
- mendelian randomization;
- SBP=
- systolic blood pressure;
- SNP=
- single nucleotide polymorphism;
- TC=
- total cholesterol;
- T2D=
- type 2 diabetes;
- MH=
- white matter hyperintensities
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
International Consortium of Blood Pressure (ICBP) coinvestigators are listed at links.lww.com/WNL/B672.
- Received March 16, 2021.
- Accepted in final form November 19, 2021.
- © 2021 American Academy of Neurology
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