Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China.
Chinese Institute for Brain Research, Beijing 102206, China.
J Clin Endocrinol Metab. 2023 Aug 18;108(9):2290-2298. doi: 10.1210/clinem/dgad114.
Observational studies have provided insufficient information on the association between thyroid function and the risk of cerebral small vessel disease (CSVD); moreover, the causality of this link is still unclear.
This study aims to investigate whether genetically predicted variation within thyroid function is causally associated with the risk of CSVD using 2-sample Mendelian randomization (MR) analysis.
In this 2-sample MR study with genome-wide association variants, we estimated the causal effects of genetically predicted thyrotropin (thyroid-stimulating hormone, TSH; n = 54 288), free thyroxine (FT4; n = 49 269), hypothyroidism (n = 51 823), and hyperthyroidism (n = 51 823) on 3 neuroimaging markers of CSVD, including white matter hyperintensity (WMH; n = 42 310), mean diffusivity (MD; n = 17 467), and fractional anisotropy (FA, n = 17 663). The primary analysis was conducted by the inverse variance-weighted MR method, followed by sensitivity analyses using MR-PRESSO, MR-Egger, weighted median, and weighted mode methods.
Genetically increased TSH was associated with increased MD (β = .311, 95% CI 0.0763, 0.548, P = .01). Genetically increased FT4 was associated with increased FA (β = .540, 95% CI 0.222, 0.858, P < .001). Sensitivity analyses using different MR methods showed similar directions but lower precision. No significant associations of hypothyroidism or hyperthyroidism with WMH, MD, or FA were found (all P > .05).
This study indicated that genetically predicted increased TSH was associated with increased MD, as well as increased FT4 with increased FA, implying the causal effect of thyroid dysfunction on white matter microstructural injury. There were no significant causal relationships of hypothyroidism or hyperthyroidism with CSVD. Further investigations should verify these findings and clarify the underlying pathophysiological mechanisms.
观察性研究提供的关于甲状腺功能与脑小血管疾病（CSVD）风险之间关联的信息不足；此外，这种联系的因果关系尚不清楚。
本研究旨在通过两样本 Mendelian 随机化（MR）分析，研究甲状腺功能的遗传预测变异是否与 CSVD 的风险有因果关系。
在这项基于全基因组关联变异的两样本 MR 研究中，我们使用两样本 Mendelian 随机化（MR）分析，估计了遗传预测的促甲状腺激素（甲状腺刺激激素，TSH；n=54288）、游离甲状腺素（FT4；n=49269）、甲状腺功能减退（n=51823）和甲状腺功能亢进（n=51823）对 3 种 CSVD 神经影像学标志物（包括脑白质高信号（WMH；n=42310）、平均弥散度（MD；n=17467）和分数各向异性（FA，n=17663）的因果效应。主要分析采用逆方差加权 MR 法，随后采用 MR-PRESSO、MR-Egger、加权中位数和加权众数法进行敏感性分析。
遗传上增加的 TSH 与 MD 增加有关（β=0.311，95%CI 0.0763，0.548，P=0.01）。遗传上增加的 FT4 与 FA 增加有关（β=0.540，95%CI 0.222，0.858，P<.001）。使用不同 MR 方法的敏感性分析显示了相似的方向，但精度较低。甲状腺功能减退或甲状腺功能亢进与 WMH、MD 或 FA 之间没有显著的关联（均 P>.05）。
本研究表明，遗传上预测的 TSH 增加与 MD 增加有关，FT4 增加与 FA 增加有关，这表明甲状腺功能障碍对脑白质微观结构损伤有因果关系。甲状腺功能减退或甲状腺功能亢进与 CSVD 之间没有显著的因果关系。进一步的研究应该验证这些发现并阐明潜在的病理生理机制。
