Deciphering causal interactions between autoimmune and thyroid diseases: a Mendelian randomization analysis

Abstract

Background

Autoimmune disorders and thyroid diseases (TDs) frequently coexist, yet their causal relationships and underlying mechanisms remain poorly characterized.

Methods

We conducted bidirectional two-sample Mendelian randomization (MR) analyses integrating univariable, multivariable, and Bayesian-weighted approaches. Genome-wide association data from 10.3 million individuals (FinnGen, UK Biobank, and public repositories) were analyzed to assess causal effects between 12 autoimmune diseases and 6 TDs. Genetic instruments were rigorously selected (p < 5 × 10^–8, F > 10, LD clumping r² < 0.001), with multivariable MR adjusting for BMI, smoking, and alcohol consumption.

Results

Autoimmune diseases demonstrated significant causal effects on hyperthyroidism (OR = 2.12, 95% CI 1.95–2.31), hypothyroidism (OR = 1.61, 1.58–1.64), and Hashimoto’s thyroiditis (OR = 1.50, 1.32–1.58). Reverse MR revealed reciprocal risks, with hyperthyroidism increasing autoimmune disease susceptibility (OR = 1.12, 1.11–1.12). Graves’ disease exhibited the strongest bidirectional associations (hyperthyroidism OR = 2.46, 2.37–2.56; reverse OR = 1.91, 1.86–1.96). Type 1 diabetes and rheumatoid arthritis showed moderate bidirectional effects (OR range: 1.12–1.95), while systemic lupus erythematosus increased papillary thyroid cancer risk (OR = 1.18, 1.08–1.28). Ankylosing spondylitis reduced hypothyroidism risk (OR = 0.97, 0.96–0.98). Multivariable MR confirmed persistence effects after covariate adjustment (OR range 1.11–4.11, all p < 0.01).

Conclusion

This MR study establishes bidirectional causality between autoimmune diseases and TDs, with disease-specific effect magnitudes. The findings advocate for:

1.	Enhanced thyroid surveillance in autoimmune patients (particularly Graves’ disease/systemic lupus erythematosus);
2.	Reciprocal autoimmune screening in thyroid disorder cohorts;
3.	Mechanistic investigations into shared pathways (e.g., human leukocyte antigen-mediated immunity).

These results provide an evidence base for developing targeted prevention strategies and dual-diagnosis clinical protocols.

Keywords

Thyroid diseases / Autoimmune disorders / Mendelian randomization / Bayesian / Causal relationships

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Funding

Youth Science Foundation of Foundation and Applied Basic Research Fund Project of Guangdong Province(2023A1515110149)