Genetic Causality of Hypothyroidism and Adverse Pregnancy Outcomes: A Combined Mendelian Randomisation Study and Bioinformatics Analysis

Abstract

Background: Observational studies have shown that hypothyroidism is strongly associated with adverse pregnancy outcomes, and that thyroxine during pregnancy comes mainly from the mother; therefore, thyroid defects in women may lead to problems such as miscarriage due to hormonal instability in early pregnancy, and foetal neurological deficits in mid- to late gestation, but whether there is a genetic causality between the two is still a matter of some controversy.

Objective: Goal to investigate the possible causal association between hypothyroidism and unfavorable pregnancy outcomes through the use of bioinformatics and Mendelian randomization (MR).

Methods: We used Mendelian randomization (MR) analyses using single nucleotide polymorphism (SNP) sites as instrumental variables to infer causal associations between exposures and outcomes. The inverse variance weighting method was primarily used in the analysis. Heterogeneity and horizontal multiplicity tests were also conducted to evaluate the results' robustness and the degree of causality. Lastly, preliminary bioinformatics analyses were conducted to investigate the underlying biological mechanisms.

Results: The resultant variance inverse weighting method found that hypothyroidism increased the risk of developing gestational hypertension (OR=1.054, 95% CI: 1.002-1.110 P=0.042) and poor foetal growth (OR=1.081, 95% CI:1.005-1.162 P=0.035). Heterogeneity tests, multiplicity tests and leave-one-out sensitivity analyses did not reveal any heterogeneity or multiplicity effects in the estimated effects of these three exposure factors on the risk of ovarian dysfunction.

Conclusion: Our research establishes genetically the causal relationship between pregnancy-related hypertension, hypothyroidism, and poor fetal growth-a relationship that could be linked to endosomal and cellular transport.

Keywords: Mendelian randomization; adverse pregnancy outcomes; hypothyroidism; integrated bioinformatics.

Figure 1

Flowchart of instrumental variable screening for MR method analysis. SNPs: single nucleotide polymorphisms.

Figure 2

Forrest plot for causal associations of hypothyroidism with adverse pregnancy outcomes based on IVW method.

Figure 3

The biological functions and Interactions of mediator genes. (A) Interaction network of genes was constructed using the STRING database. (B) The top 3 GO and KEGG enriched pathways.