Related Experiment Video
Updated: Jun 15, 2025
Author Spotlight: In Vivo Assessment of Thyroid Hormone Disruption Using the THAI Mouse Model
Published on: October 6, 2023
Testing for a causal role of thyroid hormone measurements within the normal range on human metabolism and diseases: a
Heba Alwan1, Jian'an Luan2, Alice Williamson3
1MRC 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.
Background:
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.
Methods:
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.
Findings:
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 × 10-3), thyroid cancer (odds ratio = 0.57, p-value = 2.97 × 10-4), and specific biomarkers, such as sex hormone binding globulin (β = -0.046, p-value = 1.33 × 10-6) and total cholesterol (β = 0.027, p-value = 5.80 × 10-3).
Interpretation:
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.
Funding:
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).
Related Concept Videos
01:18Functions of Thyroid Hormones
TH is indispensable for the normal development and maturation of the skeletal, muscular, and nervous systems during fetal and childhood growth. It facilitates bone mineral turnover and regulates protein synthesis in developing tissues, contributing significantly to overall growth and...
01:20Synthesis and Regulation of Thyroid Hormones
Upon reaching the thyroid gland, TSH stimulates the follicular cells' active uptake of iodide ions from the blood. The ions diffuse to the apical surface of the cells and are oxidized to iodine. The...
01:52Regression Toward the Mean
01:25Metabolic Rate
The Basal Metabolic Rate (BMR) measures the energy expended at rest.
Several factors influence...
01:20Study Designs in Epidemiology
Observational studies are those where the researcher does not intervene but rather observes natural variations. They include cross-sectional, cohort, and...
01:27Major Hormones and Their Functions
Oxytocin, produced in the hypothalamus and released by the pituitary gland, plays a role in social bonding, childbirth, and...