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

Background: 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.

Methods: 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.

Results: 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; P <
0.001) and a 0.032 SD increase in low-density lipoprotein cholesterol (LDL; P
= 0.021). Per one SD increase in normal FT4 was significantly associated with a
0.056 SD decrease in TC (P = 0.014) and a 0.072 SD decrease in LDL (P
= 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.

Conclusions:
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.