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

References

[1] BoutziosG, MoutsopoulosHM. Microinvasion of lymph nodes from papillary thyroid cancer in a patient with systemic lupus erythematosus under immunosuppression. Endocrine, 2020, 69(1): 228-229

[2] BowdenJ, Davey SmithG, HaycockPC, BurgessS. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genetic Epidemiology, 2016, 40(4): 304-314

[3] BurgessS, BowdenJ, FallT, IngelssonE, ThompsonSG. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology, 2017, 28(1): 30-42

[4] BurgessS, ButterworthA, ThompsonSG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genetic Epidemiology, 2013, 37(7): 658-665

[5] CalcaterraV, PenaginiF, RossiV, AbbattistaL, BianchiA, TurziM, et al.. Thyroid disorders and inflammatory bowel disease: An association present in adults but also in children and adolescents. Front Endocrinol (Lausanne)., 2025, 161425241

[6] Davey SmithG, HemaniG. Mendelian randomization: Genetic anchors for causal inference in epidemiological studies. Human Molecular Genetics, 2014, 23(R1): R89-98

[7] EllervikC, BoulakhL, TeumerA, MarouliE, KuśA, Buch HesgaardH, et al.. Thyroid function, diabetes, and common age-related eye diseases: A Mendelian randomization study. Thyroid, 2024, 34(11): 1414-1423

[8] EmdinCA, KheraAV, KathiresanS. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926

[9] FichnaM, MałeckiPP, MłodzikowskaM, GębarskiB, RuchałaM, FichnaP. Increased risk of endocrine autoimmunity in first-degree relatives of patients with autoimmune Addison’s disease. European Journal of Endocrinology, 2020, 183(1): 73-81

[10] GanD, GaoTS, MaL, LuH, DaiH, LiuQY, et al.. Clinical efficacy of Chinese herbal medicine formula for Graves’ hyperthyroidism: A multicentre, randomized, double-blind, placebo-controlled clinical trial. Journal of Ethnopharmacology, 2024, 338Pt 3119106

[11] GuanSY, ZhengJX, FengXY, ZhangSX, XuSZ, WangP, et al.. Global burden due to modifiable risk factors for autoimmune diseases, 1990–2021: Temporal trends and socio-demographic inequalities. Autoimmunity Reviews, 2024, 2312103674

[12] HemaniG, ZhengJ, ElsworthB, WadeKH, HaberlandV, BairdD, et al.. The MR-Base platform supports systematic causal inference across the human phenome. eLife, 2018.

[13] HuangYM, ShihLJ, HsiehTW, TsaiKW, LuKC, LiaoMT, et al.. Type 2 hypersensitivity disorders, including systemic lupus erythematosus, Sjögren’s syndrome, Graves’ disease, myasthenia gravis, immune thrombocytopenia, autoimmune hemolytic anemia, dermatomyositis, and graft-versus-host disease, are THαβ-dominant autoimmune diseases. Virulence., 2024, 1512404225

[14] HynesTR, YostEA, HartleCM, OttBJ, BerlotCH. Inhibition of G-protein βγ signaling decreases levels of messenger RNAs encoding proinflammatory cytokines in T cell receptor-stimulated CD4(+) T helper cells. Journal of Molecular Signaling, 2015, 101

[15] KatahiraM, MaedaH, TosakiT, SegawaS. The human leukocyte antigen class II gene has different contributions to autoimmune type 1 diabetes with or without autoimmune thyroid disease in the Japanese population. Diabetes Research and Clinical Practice, 2009, 85(3): 293-297

[16] LeeJY, LeeMK, LeeJH, KimK, BaeK, SohnSY. Cancer risks of patients with graves’ disease who received antithyroid drugs as initial treatment: A nationwide population-based analysis. Thyroid, 2024, 34(10): 1271-1279

[17] LinH, LuR, ShangQ, GuY, LiuY, YangY, et al.. Exploring the causal relationships between cholelithiasis, cholecystitis, cholecystectomy, and gastroesophageal reflux disease: A bidirectional two-sample Mendelian randomization study. International Journal of Surgery, 2024, 111: 932-940

[18] LiuM, LongX, FuS, ZhangY, LiuZ, XuX, et al.. Mitochondrial DNA copy number and the risk of autoimmune diseases: A Mendelian randomization study with meta-analysis. J Transl Autoimmun., 2024, 9100251

[19] MathewG, AghaR, AlbrechtJ, GoelP, MukherjeeI, PaiP, et al.. STROCSS 2021: Strengthening the reporting of cohort, cross-sectional and case-control studies in surgery. International Journal of Surgery, 2021, 96106165

[20] PapadopoulouA, ÅsvoldBO, BurgessS, KuśA, MediciM, SterenborgR, et al.. Height, autoimmune thyroid disease, and thyroid cancer: A Mendelian randomization study. Thyroid, 2023, 33(12): 1476-1482

[21] ParkSK, RyooJH, KimMH, JungJY, JungYS, KimKN, et al.. Association between eight autoimmune diseases and thyroid cancer: A nationwide cohort study. Thyroid, 2024, 34(2): 206-214

[22] ParkY, LeeHS, ParkY, MinD, YangS, KimD, et al.. Evidence for the role of STAT4 as a general autoimmunity locus in the Korean population. Diabetes/metabolism Research and Reviews, 2011, 27(8): 867-871

[23] ShaoP, LiJ, MaD, WuA, JiangJ. Thyroid storm in a patient with unknown hyperthyroidism during nonthyroidal surgery-a case report and literature review. BMC Anesthesiology, 2024, 241417

[24] VerbanckM, ChenCY, NealeB, DoR. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nature Genetics, 2018, 50(5): 693-698

[25] WangLT, HuangCY, LinCH, ChengBW, LoFS, TingWH, et al.. Graves disease is more prevalent than Hashimoto disease in children and adolescents with type 1 diabetes. Front Endocrinol (Lausanne)., 2022, 131083690

[26] YangK, LuC, ChenK, ShanZ, TengW, LiY. Association between long-term exposure to environmental fine particulate matter and the prevalence of thyroid disorders: A national cross-sectional study in China. Thyroid, 2024, 34(9): 1094-1104

[27] YavorskaOO, BurgessS. Mendelian randomization: An R package for performing Mendelian randomization analyses using summarized data. International Journal of Epidemiology, 2017, 46(6): 1734-1739

[28] ZhangY, FuL. Evaluating the causal effects between Grave’s disease and diabetes mellitus: A bidirectional Mendelian randomization study. Front Endocrinol (Lausanne)., 2024, 151420499

[29] ZhaoJ, MingJ, HuX, ChenG, LiuJ, YangC. Bayesian weighted Mendelian randomization for causal inference based on summary statistics. Bioinformatics, 2020, 36(5): 1501-1508

[30] ZhaoY, SiS, ZhangK, YuanJ, LiJ, XueF. Causal relationship between type 1 diabetes and hypothyroidism: A Mendelian randomization study. Clinical Endocrinology - Oxford, 2022, 97(6): 740-746

Funding

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

RIGHTS & PERMISSIONS

Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare