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Published Online: 14 September 2022

COVID-19 and Thyroid Function: A Bi-Directional Two-Sample Mendelian Randomization Study

Publication: Thyroid
Volume 32, Issue Number 9


Background: Thyroid dysfunction has been observed among some patients with coronavirus disease (COVID-19). It is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (or its severity) leads to the development of thyroid dysfunction, or vice versa. In this study, we examined the bi-directional causal relationship between host genetic liability to three COVID-19 phenotypes (including SARS-CoV-2 infection, hospitalized and severe COVID-19) and three thyroid dysfunction traits (including hyperthyroidism, hypothyroidism, and autoimmune thyroid disease [AITD]) and three continuous traits of thyroid hormones (including thyrotropin [TSH] and free thyroxine [fT4] within reference range, and TSH in full range).
Methods: Summary statistics from the largest available meta-analyses of human genome-wide association studies were retrieved for the following variables: SARS-CoV-2 infection (n = 1,348,701), COVID-19 hospitalization (n = 1,557,411), severe COVID-19 (n = 1,059,456), hyperthyroidism (n = 51,823), hypothyroidism (n = 53,423), AITD (n = 755,406), TSH within reference range (n = 54,288), fT4 within reference range (n = 49,269), and TSH in full range (n = 119,715). Using a two-sample Mendelian randomization (MR) approach, the inverse-variance weighted (IVW) method was adopted as the main MR analysis. Weighted median, contamination mixture, MR-Egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods were applied as sensitivity analyses.
Results: Host genetic susceptibility to SARS-CoV-2 infection was causally associated with hypothyroidism in the main IVW analysis (per doubling in prevalence of SARS-CoV-2 infection, odds ratio [OR] = 1.335; 95% confidence interval [CI]: 1.167–1.526; p = 2.4 × 10−5, surpassing the Bonferroni multiple-testing threshold). Similar causal estimates were observed in the sensitivity analyses (weighted median: OR = 1.296; CI: 1.066–1.575; p = 9 × 10−3; contamination mixture: OR = 1.356; CI: 1.095–1.818; p = 0.013; MR-Egger: OR = 1.712; CI: 1.202–2.439; p = 2.92 × 10−3, and MR-PRESSO: OR = 1.335; CI: 1.156–1.542; p = 5.73 × 10−4). Host genetic liability to hospitalized or severe COVID-19 was not associated with thyroid dysfunction or thyroid hormone levels. In the reverse direction, there was no evidence to suggest that genetic predisposition to thyroid dysfunction or genetically determined thyroid hormone levels altered the risk of the COVID-19 outcomes.
Conclusions: This bi-directional MR study supports that host response to SARS-CoV-2 viral infection plays a role in the causal association with increased risk of hypothyroidism. Long-term follow-up studies are needed to confirm the expected increased hypothyroidism risk.

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Published In

cover image Thyroid®
Volume 32Issue Number 9September 2022
Pages: 1037 - 1050
PubMed: 35734897


Published online: 14 September 2022
Published in print: September 2022
Published ahead of print: 19 July 2022
Published ahead of production: 23 June 2022


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    Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong.
    Ching-Man Tang
    Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Hong Kong.
    Ching-Lung Cheung [email protected]
    Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong.


    Address correspondence to: Ching-Lung Cheung, PhD, Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong [email protected]

    Authors' Contributions

    G.H.-Y.L. and C.-L.C. conceptualized and designed the study. G.H.-Y.L. and C.-M.T. conducted the statistical analysis. G.H.-Y.L. drafted the article. All authors were involved in interpreting the data and revising the article for final submission.

    Author Disclosure Statement

    The authors have nothing to disclose.

    Funding Information

    The work was supported by the Start-up Fund for Research Assistant Professors under the Strategic Hiring Scheme of The Hong Kong Polytechnic University, granted to G.H.-Y.L. (P0036047).

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