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:<OrderedList> <ListItem> <ItemNumber>1.</ItemNumber> <ItemContent> Enhanced thyroid surveillance in autoimmune patients (particularly Graves’ disease/systemic lupus erythematosus); </ItemContent> </ListItem> <ListItem> <ItemNumber>2.</ItemNumber> <ItemContent> Reciprocal autoimmune screening in thyroid disorder cohorts; </ItemContent> </ListItem> <ListItem> <ItemNumber>3.</ItemNumber> <ItemContent> Mechanistic investigations into shared pathways (e.g., human leukocyte antigen-mediated immunity). </ItemContent> </ListItem> </OrderedList> These results provide an evidence base for developing targeted prevention strategies and dual-diagnosis clinical protocols.

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

期刊论文
发表日期：

2025年4月21日

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Ren Jing,
Yaoli Hou,
Nan Wu,
Qian Zhang,
Shaojie Wu,
Yang Wu,
Shijian Yi

摘要

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);

Reciprocal autoimmune screening in thyroid disorder cohorts;

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.