Background Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disorder causing motor neuron degeneration, muscle paralysis, and death within 3–5 years, with a rising global prevalence. While thyroid dysfunction is implicated in the pathology of other neurodegenerative diseases, its role in ALS remains unclear due to conflicting reports from observational studies. To address this, we aimed to investigate the causal relationship between thyroid function and ALS using two-sample Mendelian Randomization (MR).

Method We performed a two-sample MR study to evaluate the bidirectional causal relationship between thyroid function traits (TSH, FT4, autoimmune hyperthyroidism, autoimmune hypothyroidism) and ALS. We used SNPs from GWAS data (TSH and FT4: n=271,040; autoimmune hyperthyroidism: n=1,828 cases/279,855 controls; autoimmune hypothyroidism: n=40,926 cases/274,069 controls; ALS: n=27,205 cases/110,881 controls). We applied the inverse-variance weighted (IVW) method as the primary analysis, with sensitivity analyses (MR-Egger, weighted median, weighted mode, MR-PRESSO) to assess pleiotropy and heterogeneity.

Results We identified a causal effect of autoimmune hyperthyroidism on reducing ALS risk (IVW OR = 0.96; 95% CI: 0.93–0.99; P = 0.03), but no associations for TSH (IVW OR = 0.99; 95% CI: 0.94–1.04; P = 0.71), FT4 (IVW OR = 1.03; 95% CI: 0.96–1.12; P = 0.36), or autoimmune hypothyroidism (IVW OR = 1.01; 95% CI: 0.98–1.05; P = 0.39) with ALS. Bidirectional analysis of genetic liability to ALS showed no causal effect on TSH (IVW OR = 0.98; 95% CI: 0.96–1.01; P = 0.65), FT4 (IVW OR = 0.98; 95% CI: 0.94–1.02; P = 0.46), autoimmune hypothyroidism (IVW OR = 0.93; 95% CI: 0.76–1.13; P = 0.59), or autoimmune hyperthyroidism (IVW OR = 1.01; 95% CI: 0.76–1.33; P = 0.78).

Conclusion We found that genetic predisposition to autoimmune hyperthyroidism may reduce ALS risk. Our findings expand the knowledge of its genetic underpinnings and lay a foundation for future research into therapeutic strategies targeting thyroid function to mitigate ALS risk.

The authors have declared no competing interest.

This study did not receive any funding

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study used data from publicly available GWAS databases, all of which adhere to established ethical guidelines.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The data used in this study were obtained from publicly available databases that adhere to ethical standards and legal requirements. Other data generated that support the findings of this study are available upon request from the corresponding author.

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