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BackgroundMore than 170 million cases of COVID-19 have been reported worldwide. It has been proposed that psychiatric disorders may be risk factors and/or consequences of COVID-19 infection. However, observational studies could be affected by confounding bias. MethodsWe performed bi-directional two-sample Mendelian randomization (MR) analysis to evaluate causal relationships between liability to COVID-19 (and severe/critical infection) and a wide range of neuropsychiatric disorders or traits. We employed the latest GWAS summary statistics from the COVID-19 Host Genetics Initiative. A variety of MR methods including those accounting for horizontal pleiotropy were used. ResultsOverall we observed evidence that liability to COVID-19 or severe infection may be causally associated with higher risks of post-traumatic stress disorder (PTSD), bipolar disorder (BD) (especially BD II), schizophrenia (SCZ), attention deficit hyperactivity disorder (ADHD) and suicidal thought (ST) when compared to the general population. On the other hand, liability to a few psychiatric traits/disorders, for example ADHD, alcohol and opioid use disorders may be causally associated with higher risks of COVID-19 infection or severe disease. In genetic correlation analysis, cannabis use disorder, ADHD, and anxiety showed significant and positive genetic correlation with critical or hospitalized infection. All the above findings passed multiple testing correction at a false discovery rate (FDR)<0.05. For pneumonia, in general we observed a different pattern of associations, with bi-directional positive associations with depression- and anxiety-related phenotypes. ConclusionsIn summary, this study provides evidence for tentative bi-directional causal associations between liability to COVID-19 (and severe infection) and a number of neuropsychiatric disorders. Further replications and prospective studies are required to verify the findings.
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BackgroundMore 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. MethodsHere 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. ResultsOverall 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. ConclusionsIn 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.
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ObjectivesCOVID-19 has become a major public health problem. There is good evidence that ACE2 is a receptor for SARS-CoV-2, and high expression of ACE2 may increase susceptibility to infection. We aimed to explore risk factors affecting susceptibility to infection and prioritize drug repositioning candidates, based on Mendelian randomization (MR) studies on ACE2 lung expression. MethodsWe conducted a phenome-wide MR study to prioritize diseases/traits and blood proteins causally linked to ACE2 lung expression in GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR, as these drugs may alter ACE2 expression and may be clinically relevant. ResultsThe most consistent finding was tentative evidence of an association between diabetes-related traits and increased ACE2 expression. Based on one of the largest GWAS on type 2 diabetes (T2DM) to date (N=898,130), T2DM was causally linked to raised ACE2 expression(p=2.91E-03;MR-IVW). Significant associations(at nominal level; p<0.05) with ACE2 expression was observed across multiple DM datasets and analytic methods, for type 1 and 2 diabetes and related traits including early start of insulin. Other diseases/traits having nominal significant associations with increased expression included inflammatory bowel disease, (ER+)breast and lung cancers, asthma, smoking and elevated ALT. We also identified drugs that may target the top-ranked proteins in MR, such as fostamatinib and zinc. ConclusionsOur analysis suggested that diabetes and related traits may increase ACE2 expression, which may influence susceptibility to infection (or more severe infection). However, none of these findings withstood rigorous multiple testing corrections (at FDR<0.05). Proteome-wide MR analyses might help uncover mechanisms underlying ACE2 expression and guide drug repositioning. Further studies are required to verify our findings.
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The outbreak of pneumonia caused by the 2019 Novel Coronavirus (2019-nCoV) was reported in Wuhan City, China. However, the clinical symptoms varied in different reports. Based on results of inter-group difference test, we found that the incidence of diarrhea differed in three recent reports. As 2019-nCoV utilizes the same cell entry receptor ACE2 as severe acute respiratory syndrome coronavirus (SARS-CoV) and ACE2 tightly controls intestinal inflammation, to trace the route of infection mediated by 2019-nCoV, we used the single-cell RNA sequencing data for analysis. We found that the ACE2 mRNA was highly expressed in the healthy human small intestine rather than the lung. Besides, single-cell RNA sequencing data showed that ACE2 was significantly elevated in the proximal and distal enterocytes, where the small intestinal epithelium is exposed to the foreign pathogen. Thus, we suspect that ACE2-expressing small intestinal epithelium cells might be vulnerable to 2019-nCoV infection when people eat infected wild animals and diarrhea may serve as an indicator for infection, suggesting that clinicians should pay more attention to patients with diarrhea during the outbreak of pneumonia.
