Causal associations of COVID-19 with health and disease outcomes: a systematic review and meta-analysis

Objectives The COVID-19 pandemic has posed a substantial threat to global health. Despite numerous clinical observations and causality investigations, understanding of the disease’s progression and recovery process following infection remains limited. This systematic review and meta-analysis evaluates the causal connections between COVID-19 and various diseases using Mendelian randomization studies to provide robust theoretical underpinnings for the development of effective rehabilitation and intervention strategies.

We systematically searched PubMed, Embase, Web of Science, and Scopus for studies on Mendelian randomization related to COVID-19 published up to October 21, 2024. We used an extensive search strategy with the keywords “Mendelian randomization” and “COVID-19”. Two pairs of coauthors independently extracted data on study characteristics, exposure, and outcomes, resolving discrepancies through discussion. We included studies that considered susceptibility to COVID-19, hospitalization, or severe infection as the exposure and disease-related effects or impacts on human health as outcomes. We assessed the quality of the included studies using the MR-STROBE criteria and extracted the relative risk (odds ratio [OR]) using a random-effects model for meta-analysis. This study is registered with PROSPERO, CRD42025615426.

Of the 1654 studies identified, 87 met the inclusion criteria for our meta-analysis. The primary outcome suggests that COVID-19 is associated with an increased risk of cardio-cerebral vascular diseases. Subgroup analyses identified an increased risk of neuropsychiatric disorders, including optic nerve disorders, epilepsy, schizophrenia, generalized anxiety disorder, stroke, myocardial infarction with COVID-19. There is also a notable association between COVID-19 and the immune system, particularly neuromyelitis optica spectrum disorders and myasthenia gravis.

This study demonstrates that COVID-19 infection has direct causal effects on human health or certain diseases at the genetic level, which may manifest as increased or decreased susceptibility to disease and changes in disease severity. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was funded by the Zhejiang Medical and Health Science and Technology Project (No.2024KY484), the Shaoxing Health Science and Technology Project (No.2023SKY073), the Science and Technology Planning Project of Shaoxing City (No. 2023A14030), and Shaoxing University Enterprise Important Horizontal Topic (No. 2024USXH287) Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Author's ORCID ID updated; Manuscript updated. Data Availability All data produced in the present study are available upon reasonable request to the authors All data produced in the present work are contained in the manuscript