MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK; University of Bern, Institute of Primary Health Care (BIHAM), Bern, Switzerland; University of Bern, Graduate School for Health Sciences, Bern, Switzerland.
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
EBioMedicine. 2024 Sep;107:105306. doi: 10.1016/j.ebiom.2024.105306. Epub 2024 Aug 26.
Variation in thyroid function parameters within the normal range has been observationally associated with adverse health outcomes. Whether those associations reflect causal effects is largely unknown.
We systematically tested associations between genetic differences in thyrotropin (TSH) and free thyroxine (FT4) within the normal range and more than 1100 diseases and more than 6000 molecular traits (metabolites and proteins) in three large population-based cohorts. This was performed by combining individual and summary level genetic data and using polygenic scores and Mendelian randomization (MR) methods. We performed a phenome-wide MR study in the OpenGWAS database covering thousands of complex phenotypes and diseases.
Genetically predicted TSH or FT4 levels within the normal range were predominately associated with thyroid-related outcomes, like goitre. The few extra-thyroidal outcomes that were found to be associated with genetic liability towards high but normal TSH levels included atrial fibrillation (odds ratio = 0.92, p-value = 2.13 × 10), thyroid cancer (odds ratio = 0.57, p-value = 2.97 × 10), and specific biomarkers, such as sex hormone binding globulin (β = -0.046, p-value = 1.33 × 10) and total cholesterol (β = 0.027, p-value = 5.80 × 10).
In contrast to previous studies that have described the association with thyroid hormone levels and disease outcomes, our genetic approach finds little evidence of an association between genetic differences in thyroid function within the normal range and non-thyroidal phenotypes. The association described in previous studies may be explained by reverse causation and confounding.
This research was funded by the Swiss National Science Foundation (P1BEP3_200041). The Fenland study (DOI 10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1, MC_PC_13046 and MC_UU_00006/1). The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-UU_12015/1, MC_PC_13048 and MC_UU_00006/1).
甲状腺功能参数在正常范围内的变化与不良健康结果已有观察性关联。这些关联是否反映了因果效应，在很大程度上尚不清楚。
我们系统地测试了三个大型基于人群的队列中，促甲状腺激素（TSH）和游离甲状腺素（FT4）在正常范围内的遗传差异与 1100 多种疾病和 6000 多种分子特征（代谢物和蛋白质）之间的关联。通过结合个体和汇总水平的遗传数据以及使用多基因评分和孟德尔随机化（MR）方法来实现这一点。我们在 OpenGWAS 数据库中进行了一项表型广泛的 MR 研究，涵盖了数千种复杂表型和疾病。
在正常范围内，遗传预测的 TSH 或 FT4 水平主要与甲状腺相关的结果相关，如甲状腺肿。发现与高但正常 TSH 水平的遗传易感性相关的少数额外的甲状腺外结果包括心房颤动（比值比=0.92，p 值=2.13×10）、甲状腺癌（比值比=0.57，p 值=2.97×10）和特定的生物标志物，如性激素结合球蛋白（β=-0.046，p 值=1.33×10）和总胆固醇（β=0.027，p 值=5.80×10）。
与先前描述甲状腺激素水平与疾病结果之间关联的研究不同，我们的遗传方法几乎没有发现甲状腺功能正常范围内的遗传差异与非甲状腺表型之间存在关联的证据。先前研究中描述的关联可能可以通过反向因果关系和混杂因素来解释。
这项研究由瑞士国家科学基金会（P1BEP3_200041）资助。Fenland 研究（DOI 10.22025/2017.10.101.00001）由医学研究理事会（MC_UU_12015/1、MC_PC_13046 和 MC_UU_00006/1）资助。EPIC-Norfolk 研究（DOI 10.22025/2019.10.105.00004）得到了医学研究理事会（MR/N003284/1、MC-UU_12015/1、MC_PC_13048 和 MC_UU_00006/1）的资助。
