Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Challenges in interpreting Mendelian randomization studies with a disease as the exposure: Using COVID-19 liability studies as an exemplar

European Journal of Human Genetics volume 33, pages 658–665 (2025)Cite this article

Subjects

Abstract

Mendelian randomization (MR) studies using diseases as exposures are increasingly prevalent although any observed associations do not necessarily imply effect of diseases. To illustrate this challenge, we conducted a systematic review of MR studies focusing on COVID-19 consequence. We hypothesized if outcome genome-wide association studies (GWAS) were conducted before COVID-19 pandemic in late 2019, any observed associations in these studies were unlikely to be driven by COVID-19. We systematically searched PubMed, EMBASE, and MEDLINE for all MR studies published between 1 January 2019 and 20 May 2023. Inclusion criteria included MR studies which used COVID-19 as the exposure and designed to assess COVID-19’s impact on health outcomes. We extracted relevant information, such as result interpretation and relevance assumption assessment. This review was registered at PROSPERO (CRD42023421079). Amongst 57 included studies, 45 studies used outcome GWAS published prior to 2019 whilst the remaining studies likely used outcome GWAS containing data collected before 2019. Relevance assumption was assessed mainly by p values. A total of 35 studies showed an association of COVID-19 liability with health outcomes. Regardless of the results, 45 studies attributed these as evidence (or lack of evidence) of COVID-19 consequence. In MR studies using disease liability as exposure, relevance assumption should consider the prevalence of the disease in the outcome GWAS in the context of 2 sample Mendelian randomization study rather than p values/F-statistic alone. Even when these are verified, these studies likely suffered from pleiotropy, making corresponding interpretation as effect of disease challenging.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2: Summary of the results included in this review.
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The data from this systematic review were extracted from existing publications of Mendelian randomization studies.

References

  1. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Morris AP, Voight BF, Teslovich TM, Ferreira T, Segre AV, Steinthorsdottir V, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012;44:981–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, et al. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature. 2024;627:347–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zeng P, Wang T, Zheng J, Zhou X. Causal association of type 2 diabetes with amyotrophic lateral sclerosis: new evidence from Mendelian randomization using GWAS summary statistics. BMC Med. 2019;17:225.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Pan Y, Wang Y, Wang Y. Investigation of Causal Effect of Atrial Fibrillation on Alzheimer Disease: A Mendelian Randomization Study. J Am Heart Assoc. 2020;9:e014889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Budu-Aggrey A, Joyce S, Davies NM, Paternoster L, Munafo MR, Brown SJ, et al. Investigating the causal relationship between allergic disease and mental health. Clin Exp Allergy. 2021;51:1449–58.

    Article  CAS  PubMed  Google Scholar 

  7. De Silva NMG, Borges MC, Hingorani AD, Engmann J, Shah T, Zhang X, et al. Liver Function and Risk of Type 2 Diabetes: Bidirectional Mendelian Randomization Study. Diabetes. 2019;68:1681–91.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Au Yeung SL, Borges MC, Lawlor DA, Schooling CM. Impact of lung function on cardiovascular diseases and cardiovascular risk factors: a two sample bidirectional Mendelian randomisation study. Thorax. 2022;77:164–71.

    Article  PubMed  Google Scholar 

  9. Burgess S, Labrecque JA. Mendelian randomization with a binary exposure variable: interpretation and presentation of causal estimates. Eur J Epidemiol. 2018;33:947–52.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Leppert B, Riglin L, Wootton RE, Dardani C, Thapar A, Staley JR, et al. The Effect of Attention Deficit/Hyperactivity Disorder on Physical Health Outcomes: A 2-Sample Mendelian Randomization Study. Am J Epidemiol. 2021;190:1047–55.

    Article  PubMed  Google Scholar 

  11. Wu X, Zhang W, Zhao X, Zhang L, Xu M, Hao Y, et al. Investigating the relationship between depression and breast cancer: observational and genetic analyses. BMC Med. 2023;21:170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Holmes MV, Davey Smith G. Can Mendelian Randomization Shift into Reverse Gear? Clin Chem. 2019;65:363–6.

    Article  CAS  PubMed  Google Scholar 

  13. Brenowitz WD, Zimmerman SC, Filshtein TJ, Yaffe K, Walter S, Hoffmann TJ, et al. Extension of Mendelian Randomization to Identify Earliest Manifestations of Alzheimer Disease: Association of Genetic Risk Score for Alzheimer Disease With Lower Body Mass Index by Age 50 Years. Am J Epidemiol. 2021;190:2163–71.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bell JA, Bull CJ, Gunter MJ, Carslake D, Mahajan A, Davey Smith G, et al. Early Metabolic Features of Genetic Liability to Type 2 Diabetes: Cohort Study With Repeated Metabolomics Across Early Life. Diabetes Care. 2020;43:1537–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Smith ML, Bull CJ, Holmes MV, Davey Smith G, Sanderson E, Anderson EL, et al. Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study. EBioMedicine. 2023;90:104503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Au Yeung SL, Jiang C, Cheng KK, Liu B, Zhang W, Lam TH, et al. Is aldehyde dehydrogenase 2 a credible genetic instrument for alcohol use in Mendelian randomization analysis in Southern Chinese men? Int J Epidemiol. 2013;42:318–28.

    Article  PubMed  Google Scholar 

  17. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6:e1000100.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Skrivankova VW, Richmond RC, Woolf BAR, Yarmolinsky J, Davies NM, Swanson SA, et al. Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization: The STROBE-MR Statement. JAMA. 2021;326:1614–21.

    Article  PubMed  Google Scholar 

  20. Luo S, Liang Y, Wong THT, Schooling CM, Au Yeung SL. Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies. Int J Epidemiol. 2022;51:1088–105.

    Article  PubMed  Google Scholar 

  21. Niemi MEK, Karjalainen J, Liao RG, Neale BM, Daly M, Ganna A, et al. Mapping the human genetic architecture of COVID-19. Nature. 2021;600:472–7.

    Article  CAS  Google Scholar 

  22. Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, Invernizzi P, et al. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med. 2020;383:1522–34.

    Article  CAS  PubMed  Google Scholar 

  23. Pairo-Castineira E, Clohisey S, Klaric L, Bretherick AD, Rawlik K, Pasko D, et al. Genetic mechanisms of critical illness in COVID-19. Nature. 2021;591:92–8.

    Article  PubMed  Google Scholar 

  24. Jia M, Chen HJ, Jia LM, Chen YL. Genetic Predisposition to Coronavirus Disease 2019 in Relation to Ten Cardiovascular Conditions: A Two-Sample Mendelian Randomization Study. Front Med. 2022;9:796165.

    Article  Google Scholar 

  25. Luykx JJ, Lin BD. Are psychiatric disorders risk factors for COVID-19 susceptibility and severity? a two-sample, bidirectional, univariable, and multivariable Mendelian Randomization study. Transl Psychiatry. 2021;11:210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li J, Bai H, Qiao H, Du C, Yao P, Zhang Y, et al. Causal effects of COVID-19 on cancer risk: A Mendelian randomization study. J Med Virol. 2023;95:e28722.

    Article  CAS  PubMed  Google Scholar 

  27. Liu D, Zhang Q, Bai P, Zhao J. Assessing causal relationships between COVID-19 and non-alcoholic fatty liver disease. J Hepatol. 2022;76:740–2.

    Article  CAS  PubMed  Google Scholar 

  28. Ran S, Pan L, Liu B. Are patients with systemic lupus erythematosus at increased risk for COVID-19? A bi-directional Mendelian randomisation study. Lupus Sci Med. 2022;9:e000786.

  29. Gao R, Xu Y, Zhu G, Zhou S, Li H, Han G, et al. Genetic variation associated with COVID-19 is also associated with endometrial cancer. J Infect. 2022;84:e85–e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Miao JP, Gu XY, Shi RZ. COVID-19 is associated with the risk of cardiovascular disease death: A two-sample Mendelian randomization study. Front Cardiovasc Med. 2022;9:974944.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Baranova A, Cao H, Zhang F. Causal effect of COVID-19 on Alzheimer’s disease: A Mendelian randomization study. J Med Virol. 2023;95:e28107.

    Article  CAS  PubMed  Google Scholar 

  32. Tan JS, Liu NN, Guo TT, Hu S, Hua L. Genetic predisposition to COVID-19 may increase the risk of hypertension disorders in pregnancy: A two-sample Mendelian randomization study. Pregnancy Hypertens. 2021;26:17–23.

    Article  PubMed  Google Scholar 

  33. Gao X, Wei T, Wang H, Sui R, Liao J, Sun D, et al. Causal associations between obstructive sleep apnea and COVID-19: A bidirectional Mendelian randomization study. Sleep Med. 2023;101:28–35.

    Article  PubMed  Google Scholar 

  34. Zhang Z, Fang T, Lv Y. Causal associations between thyroid dysfunction and COVID-19 susceptibility and severity: A bidirectional Mendelian randomization study. Front Endocrinol. 2022;13:961717.

    Article  Google Scholar 

  35. Au Yeung SL, Jiang CQ, Cheng KK, Liu B, Zhang WS, Lam TH, et al. Evaluation of moderate alcohol use and cognitive function among men using a Mendelian randomization design in the Guangzhou biobank cohort study. Am J Epidemiol. 2012;175:1021–8.

    Article  CAS  PubMed  Google Scholar 

  36. Rosenberg NA, Huang L, Jewett EM, Szpiech ZA, Jankovic I, Boehnke M. Genome-wide association studies in diverse populations. Nat Rev Genet. 2010;11:356–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Au Yeung SL, Zhao JV, Schooling CM. Evaluation of glycemic traits in susceptibility to COVID-19 risk: a Mendelian randomization study. BMC Med. 2021;19:72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Leong A, Cole JB, Brenner LN, Meigs JB, Florez JC, Mercader JM. Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis. PLoS Med. 2021;18:e1003553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fernandez-Gallego N, Castillo-Gonzalez R, Mendez-Barbero N, Lopez-Sanz C, Obeso D, Villasenor A, et al. The impact of type 2 immunity and allergic diseases in atherosclerosis. Allergy. 2022;77:3249–66.

    Article  CAS  PubMed  Google Scholar 

  40. Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16:358–72.

    Article  CAS  PubMed  Google Scholar 

  41. Levey DF, Galimberti M, Deak JD, Wendt FR, Bhattacharya A, Koller D, et al. Multi-ancestry genome-wide association study of cannabis use disorder yields insight into disease biology and public health implications. Nat Genet. 2023;55:2094–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fischer B, Lindner SR, Hall W. Cannabis use and public health: time for a comprehensive harm-to-others framework. Lancet Public Health. 2022;7:e808–e9.

    Article  PubMed  Google Scholar 

  43. UN Publication. World Drug Report 2022. Vienna: United Nations Office on Drugs and Crime; 2022.

  44. Chapman SJ, Hill AV. Human genetic susceptibility to infectious disease. Nat Rev Genet. 2012;13:175–88.

    Article  CAS  PubMed  Google Scholar 

  45. Stein CM. Genetic epidemiology of tuberculosis susceptibility: impact of study design. PLoS Pathog. 2011;7:e1001189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bostock CV, Soiza RL, Whalley LJ. Genetic determinants of ageing processes and diseases in later life. Maturitas. 2009;62:225–9.

    Article  CAS  PubMed  Google Scholar 

  47. Cheung CL, Ho SC, Krishnamoorthy S, Li GH. COVID-19 and platelet traits: A bidirectional Mendelian randomization study. J Med Virol. 2022;94:4735–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li M, Yeung CHC, Schooling CM. Circulating Cytokines and Coronavirus Disease: A Bi-Directional Mendelian Randomization Study. Front Genet. 2021;12:680646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhu G, Zhou S, Xu Y, Gao R, Li H, Su W, et al. Mendelian randomization study on the causal effects of COVID-19 on childhood intelligence. J Med Virol. 2022;94:3233–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang K, Gao H, Chen M. Genetic susceptibility to COVID-19 may increase the risk of erectile dysfunction: A two-sample Mendelian randomization study. Andrologia. 2022;54:e14527.

    Article  CAS  PubMed  Google Scholar 

  51. Cao H, Baranova A, Wei X, Wang C, Zhang F. Bidirectional causal associations between type 2 diabetes and COVID-19. J Med Virol. 2023;95:e28100.

    Article  CAS  PubMed  Google Scholar 

  52. Kjaergaard AD, Smith GD, Stewart P. Mendelian Randomization Studies in Endocrinology: Raising the Quality Bar for Submissions and Publications in The Journal of Clinical Endocrinology & Metabolism. J Clin Endocrinol Metab. 2024;109:1–3.

    Article  Google Scholar 

  53. Au Yeung SL, Gill D. Standardizing the reporting of Mendelian randomization studies. BMC Med. 2023;21:187.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Au Yeung SL, Gill D. Concerns over using the Mendelian randomization design to investigate the effect of air pollution. Sci Total Environ. 2024;917:170474.

    Article  CAS  PubMed  Google Scholar 

  55. Reed ZE, Wootton RE, Khouja JN, Richardson TG, Sanderson E, Davey Smith G, et al. Exploring pleiotropy in Mendelian randomisation analyses: What are genetic variants associated with ‘cigarette smoking initiation’ really capturing? Genet Epidemiol. 2025;49:e22583.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

There is no funding for this study.

Author information

Author notes

  1. These authors contributed equally: Siyu Chen, Ying Liang.

  2. These authors jointly supervised this work: Stephen Burgess, Shiu Lun Au Yeung.

Authors and Affiliations

  1. School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China

    Siyu Chen, Ying Liang, Jacky Man Yuen Mo, Queenie Ho Yi Li, Baoting He & Shiu Lun Au Yeung

  2. MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, United Kingdom

    Stephen Burgess

  3. Department of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China

    Shan Luo

Authors
  1. Siyu Chen
    View author publications

    Search author on:PubMed Google Scholar

  2. Ying Liang
    View author publications

    Search author on:PubMed Google Scholar

  3. Jacky Man Yuen Mo
    View author publications

    Search author on:PubMed Google Scholar

  4. Queenie Ho Yi Li
    View author publications

    Search author on:PubMed Google Scholar

  5. Baoting He
    View author publications

    Search author on:PubMed Google Scholar

  6. Shan Luo
    View author publications

    Search author on:PubMed Google Scholar

  7. Stephen Burgess
    View author publications

    Search author on:PubMed Google Scholar

  8. Shiu Lun Au Yeung
    View author publications

    Search author on:PubMed Google Scholar

Contributions

SLAY designed this study, with feedback from SB. SC and YL performed the systematic review, data extraction and compilation, with the help of SLAY and JMMY. SLAY and SC wrote the first draft of the manuscript with critical feedback and revisions from YL, QHYL, BH, SL and SB. All authors gave final approval of the version to be published. SC and SLAY are the guarantors of the study.

Corresponding author

Correspondence to Shiu Lun Au Yeung.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, S., Liang, Y., Mo, J.M.Y. et al. Challenges in interpreting Mendelian randomization studies with a disease as the exposure: Using COVID-19 liability studies as an exemplar. Eur J Hum Genet 33, 658–665 (2025). https://doi.org/10.1038/s41431-025-01840-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41431-025-01840-x

This article is cited by

Search

Advanced search

Quick links