Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Thyroid. 2021 Aug;31(8):1171-1181. doi: 10.1089/thy.2020.0884. Epub 2021 May 26.
Observational studies suggest that even minor variations in thyroid function are associated with the risk of mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD). However, it is unknown whether these associations are causal or not. We used a Mendelian randomization (MR) approach to investigate causal effects of minor variations in thyrotropin (TSH) and free thyroxine (fT4) levels on MDD and BD risk. We performed two-sample MR analyses using data from the largest publicly available genome-wide association studies on normal-range TSH ( = 54,288) and fT4 ( = 49,269) levels, MDD (170,756 cases, 329,443 controls) and BD (20,352 cases, 31,358 controls). Secondary MR analyses investigated the effects of TSH and fT4 levels on specific MDD and BD subtypes. Reverse MR was also performed to assess the effects of MDD and BD on TSH and fT4 levels. There were no associations between genetically predicted TSH and fT4 levels and MDD risk, nor MDD subtypes and minor depressive symptoms. A one standard deviation increase in fT4 levels was nominally associated with an 11% decrease in the overall BD risk (odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.80-0.98, = 0.022) and a 13% decrease in the BD type 1 risk (OR = 0.87, CI = 0.75-1.00, = 0.047). In the reverse direction, genetic predisposition to MDD and BD was not associated with TSH nor fT4 levels. Variations in normal-range TSH and fT4 levels have no effects on the risk of MDD and its subtypes, and neither on minor depressive symptoms. This indicates that depressive symptoms should not be attributed to minor variations in thyroid function. Borderline associations with BD and BD type 1 risks suggest that further clinical studies should investigate the effect of thyroid hormone treatment in BD.
观察性研究表明，即使甲状腺功能的微小变化也与情绪障碍的风险相关，包括重度抑郁症（MDD）和双相情感障碍（BD）。然而，这些关联是否具有因果关系尚不清楚。我们使用孟德尔随机化（MR）方法来研究促甲状腺激素（TSH）和游离甲状腺素（fT4）水平的微小变化对 MDD 和 BD 风险的因果影响。我们使用来自最大的公开全基因组关联研究中正常范围 TSH（ = 54,288）和 fT4（ = 49,269）水平、MDD（170,756 例，329,443 例对照）和 BD（20,352 例，31,358 例对照）的数据进行了两样本 MR 分析。次要 MR 分析研究了 TSH 和 fT4 水平对特定 MDD 和 BD 亚型的影响。还进行了反向 MR 以评估 MDD 和 BD 对 TSH 和 fT4 水平的影响。遗传预测的 TSH 和 fT4 水平与 MDD 风险之间没有关联，也与 MDD 亚型和轻度抑郁症状无关。fT4 水平增加一个标准差，BD 总体风险降低 11%（比值比 [OR] = 0.89，95%置信区间 [CI] = 0.80-0.98， = 0.022），BD 1 型风险降低 13%（OR = 0.87，CI = 0.75-1.00， = 0.047）。在相反的方向上，MDD 和 BD 的遗传易感性与 TSH 或 fT4 水平无关。正常范围内 TSH 和 fT4 水平的变化对 MDD 及其亚型的风险没有影响，也不会影响轻度抑郁症状。这表明抑郁症状不应归因于甲状腺功能的微小变化。与 BD 和 BD 1 型风险的边缘关联表明，应进一步进行临床研究以调查甲状腺激素治疗在 BD 中的作用。
