The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China.
The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, Zhejiang, China.
J Stroke Cerebrovasc Dis. 2024 Oct;33(10):107923. doi: 10.1016/j.jstrokecerebrovasdis.2024.107923. Epub 2024 Aug 10.
Neuroticism was found to be associated with cerebral small vessel disease (CSVD) in observational studies. We aimed to explore the causal relationship between distinct components of neuroticism and CSVD.
Two-sample mendelian randomization (MR) study was conducted to explore the bidirectional causal relationships between three genetically distinct subclusters of neuroticism (depressed affect, worry, and sensitivity to environmental stress and adversity [SESA]) and MRI markers of CSVD using publicly available genome-wide association studies (GWAS) data. Inverse variance weighted (IVW) method was used for the primary causal estimates. Alternative MR approaches and extensive sensitivity analyses were conducted to ensure the robustness of the findings. Multivariable MR (MVMR) analysis was used to estimate the direct causal effects with adjustment of other known risk factors for CSVD.
Genetically determined SESA was significantly associated with reduced fractional anisotropy (FA) (beta: -1.94, 95%CI: -3.04 to -0.84, p=5.29e-4), and associated with increased mean diffusivity (MD) (beta=1.55, 95%CI: 0.29 to 2.81, p=0.016) and white matter hyperintensities (WMH) (beta=0.25, 95% CI: 0.03 to 0.47, p=0.029) at the nominally significant level. MVMR analysis suggested the significant associations remained significant after accounting for body mass index (BMI), smoking, alcohol drinking, type 2 diabetes (T2D), hypertension, and depression. The other two neuroticism subclusters (depressed affect and worry) didn't have significant causal effects on the MRI markers. In the reverse MR analysis with the MRI markers as exposures, no significant associations were found.
This study supported the casual role of SESA in the development of CSVD. Further research to explore the underlying mechanism are warranted.
观察性研究发现神经质与脑小血管疾病（CSVD）有关。我们旨在探索神经质的不同成分与 CSVD 之间的因果关系。
采用双样本孟德尔随机化（MR）研究，利用公开的全基因组关联研究（GWAS）数据，探讨三种遗传上不同的神经质亚群（抑郁、担忧和对环境压力和逆境的敏感性[SESA]）与 CSVD 的 MRI 标志物之间的双向因果关系。采用逆方差加权（IVW）法进行主要因果估计。进行了替代 MR 方法和广泛的敏感性分析，以确保研究结果的稳健性。采用多变量 MR（MVMR）分析来估计直接因果效应，并调整其他已知的 CSVD 风险因素。
遗传决定的 SESA 与分数各向异性（FA）降低显著相关（β：-1.94，95%CI：-3.04 至-0.84，p=5.29e-4），与平均扩散系数（MD）增加显著相关（β=1.55，95%CI：0.29 至 2.81，p=0.016）和脑白质高信号（WMH）增加显著相关（β=0.25，95%CI：0.03 至 0.47，p=0.029），均达到名义显著水平。MVMR 分析表明，在考虑体重指数（BMI）、吸烟、饮酒、2 型糖尿病（T2D）、高血压和抑郁后，这些显著关联仍然显著。其他两个神经质亚群（抑郁和担忧）对 MRI 标志物没有显著的因果影响。在以 MRI 标志物为暴露因素的反向 MR 分析中，未发现显著关联。
本研究支持 SESA 在 CSVD 发展中的因果作用。需要进一步研究来探索潜在的机制。
