Exploring causal relationships between COVID-19 and cardiometabolic disorders: A bi-directional Mendelian randomization study

Abstract

Background: More than 100 million cases of COVID-19 have been reported worldwide. A number of risk factors for infection or severe infection have been identified, however observational studies were subject to confounding bias. In addition, there is still limited knowledge about the complications or medical consequences of the disease. Methods: Here we performed bi-directional Mendelian randomization (MR) analysis to evaluate causal relationships between liability to COVID-19 (and severe/critical infection) and a wide range of around 30 cardiometabolic disorders (CMD) or traits. Genetic correlation (rg) was assessed by LD score regression(LDSC). The latest GWAS summary statistics from the COVID-19 Host Genetics Initiative was used, which comprised comparisons of general population controls with critically ill, hospitalized and any infected cases. Results: Overall we observed evidence that liability to COVID-19 or severe infection may be causally associated with higher risks of type 2 diabetes mellitus(T2DM), chronic kidney disease(CKD), ischemic stroke (especially large artery stroke[LAS]) and heart failure(HF) when compared to the general population. On the other hand, our findings suggested that liability to atrial fibrillation (AF), stroke (especially LAS), obesity, diabetes (T1DM and T2DM), low insulin sensitivity and impaired renal function (low eGFR and diabetic kidney disease) may be causal risk factors for COVID-19 or severe disease. In genetic correlation analysis, T2DM, CAD, obesity, fasting insulin, CKD, gout, stroke and urate showed positive rg with critical or hospitalized infection. All above findings passed multiple testing correction at a false discovery rate (FDR)<0.05. Conclusions: In summary, this study provides evidence for tentative bi-directional causal associations between liability to COVID-19 and severe disease and a number of CM disorders. Further replications and prospective studies are required to verify the findings.

Neuropsychiatric disorders as risk factors and consequences of COVID-19: A Mendelian randomization study

“…Another study 19 showed that type I error is controlled at the nominal rate when MR is conducted with up to ∼900 SNPs which fell short of genome-wide significance. We have also conducted extensive simulations earlier 20 and have showed that relaxation of the p-value threshold (pthres) up to 0.01 does not lead to increased rate of false positive findings. Based on the above studies and recent advances, here we also considered more liberal pthres for instrument inclusion to improve power.…”

“…There are other limitations of the MR methodology. For more detailed discussions of the strengths and shortcomings of MR, please also refer to other papers 20, 55-57 . For example, horizontal pleiotropy (the instrumental SNP being associated with the outcome via another pathway not through the exposure) may affect the validity of results, which can be accounted for by some MR methods 58, 59 .…”

Association of COVID-19 with risks of hospitalization and mortality from other disorders post-infection: A study of the UK Biobank

“…While this is an observational study, it is interesting to note that Mendelian randomization studies, which are less prone to confounding, have also shown that COVID-19 may be a causal risk factor for various cardiometabolic and neuropsychiatric disorders 44,45 .…”

Commentary: A Machine-Generated View of the Role of Blood Glucose Levels in the Severity of COVID-19. A Metabolic Endocrinology Perspective

“…There have been many retrospective follow-up cohort studies of COVID-19 cases that have generally reported an increase in the severity of existing diabetes and in the incidence of new-onset diabetes in the post-acute phase ( 24 – 30 ). There has also been a bidirectional Mendelian randomization study that established a potential causal effect of COVID-19 on the subsequent risk of new-onset type 2 diabetes ( 31 ). These reports of new-onset diabetes in the post-acute phase would fall within the WHO definition of long-COVID if the diabetes were a direct consequence of COVID-19.…”