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.

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.

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.

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.

心血管危险因素与脑小血管病（CSVD）的病因有关；然而，这些关联是否是因果关系仍不清楚，部分原因是观察性研究容易逆转因果关系和混淆。在这里，我们使用孟德尔随机化 (MR) 来确定哪些心血管危险因素可能与 CSVD 的病因有关。

我们使用来自欧洲血统的大规模全基因组关联研究的数据来确定血压、血脂、体重指数 (BMI)、2 型糖尿病、吸烟开始、每天吸烟和饮酒的遗传代理。使用来自 UK Biobank (N = 31,855) 的遗传摘要数据，进行 MR 以评估它们与 CSVD 中改变的 3 个神经影像学特征（白质高信号 [WMH]、分数各向异性 [FA] 和平均扩散率 [MD]）的关联. 我们的主要分析使用反向加权中位数 MR，并使用加权中位数、MR-Egger 和多效性最小化方法进行验证。最后，进行多变量MR以联合研究多个危险因素的影响。

MR 分析显示，在所有方法中，较高的遗传代理收缩压和舒张压与 WMH、FA 和 MD 以及较高的遗传代理 BMI 与 WMH 相关。总胆固醇、低密度脂蛋白、吸烟开始、脉压和 2 型糖尿病易感性与至少 1 项 CSVD 成像特征之间的关联证据较弱，但这些关联在所使用的所有验证方法中均无法重现。对血压特征的多变量 MR 分析发现，这种影响主要是通过所有 CSVD 特征的基因替代舒张压。

高血压（主要是舒张压）和 BMI 较高的遗传易感性与 CSVD 的较高负担相关，这表明存在因果关系。改进对这些风险因素的管理和治疗可以减轻 CSVD 的负担。