Mendelian randomization highlights the causal role of normal thyroid function on blood lipid profiles

<b>Background:</b> The association between thyroid function and dyslipidemia has been well documented in observational studies. However, observational studies are prone to confounding, making it difficult to make causal inference and determine the direction of these associations. <b>Methods:</b> We performed a two-sample bi-directional Mendelian randomization (MR) using summary statistics from large-scale genome-wide association studies (GWASs) of thyroid stimulating hormone (TSH), free thyroxine (FT4) and blood lipids. We chose inverse variance weighted (IVW) method as main analysis, and consolidated results through various sensitivity analyses involving six different MR methods under different model specifications. We further conducted genetic correlation analysis and colocalization analysis to deeply reflect the causality. <b>Results:</b> The IVW method showed per one standard deviation (SD) increase in normal TSH was significantly associated with a 0.048 SD increase in total cholesterol (TC; <i>P</i> &lt; 0.001) and a 0.032 SD increase in low-density lipoprotein cholesterol (LDL; <i>P</i> = 0.021). Per one SD increase in normal FT4 was significantly associated with a 0.056 SD decrease in TC (<i>P</i> = 0.014) and a 0.072 SD decrease in LDL (<i>P</i> = 0.009). Neither TSH nor FT4 showed causal associations with high-density lipoprotein cholesterol (HDL) and triglycerides (TG). No significant causal effect of blood lipids on normal TSH or FT4 can be detected. All results were largely consistent when using several alternative MR methods, and were re-confirmed by both genetic correlation analysis and colocalization analysis. <b>Conclusions:</b> Even within reference range, higher TSH or lower FT4 are causally associated with increased TC and LDL, while no reverse causal association can be found.<br>

<b>研究背景：</b> 甲状腺功能与血脂异常之间的关联已在观察性研究中得到充分证实。然而，观察性研究易受混杂偏倚影响，难以开展因果推断并明确此类关联的方向。<br><b>研究方法：</b> 本研究利用促甲状腺激素（thyroid stimulating hormone, TSH）、游离甲状腺素（free thyroxine, FT4）及血脂的大规模全基因组关联研究（genome-wide association studies, GWAS）的汇总统计数据，开展双向两样本孟德尔随机化（Mendelian randomization, MR）分析。以逆方差加权（inverse variance weighted, IVW）法作为主要分析方法，并通过六种不同模型设定下的多种MR方法开展敏感性分析以整合验证研究结果。此外，本研究进一步开展遗传相关分析与共定位分析，以深入验证因果关联。<br><b>研究结果：</b> IVW法分析显示，正常范围内TSH每升高1个标准差（standard deviation, SD），总胆固醇（total cholesterol, TC）升高0.048 SD（<i>P</i> &lt; 0.001），低密度脂蛋白胆固醇（low-density lipoprotein cholesterol, LDL）升高0.032 SD（<i>P</i> = 0.021）。正常范围内FT4每升高1个SD，TC降低0.056 SD（<i>P</i> = 0.014），LDL降低0.072 SD（<i>P</i> = 0.009）。TSH与FT4均与高密度脂蛋白胆固醇（high-density lipoprotein cholesterol, HDL）及甘油三酯（triglycerides, TG）无显著因果关联。未检测到血脂对正常范围内TSH或FT4存在显著因果效应。采用多种替代MR方法分析所得结果整体一致，且经遗传相关分析与共定位分析进一步验证。<br><b>研究结论：</b> 即便处于参考范围内，较高的TSH水平或较低的FT4水平仍与TC、LDL升高存在因果关联，而未发现反向的因果关联。<br>