Large-scale genetic correlation studies explore the causal relationship and potential mechanism between gut microbiota and COVID-19-associated risks.

Recent observational studies suggest that gut microorganisms are involved in the onset and development of coronavirus disease 2019 (COVID-19), but the potential causal relationship behind them remains unclear. Exposure data were derived from the MiBioGen consortium, encompassing 211 gut microbiota (n = 18,340). The outcome data were sourced from the COVID-19 host genetics initiative (round 7), including COVID-19 severity (n = 1,086,211), hospitalization (n = 2,095,324), and susceptibility (n = 2,597,856). First, a two-sample Mendelian randomization (TSMR) was performed to investigate the causal effect between gut microbiota and COVID-19 outcomes. Second, a two-step MR was used to explore the potential mediators and underlying mechanisms. Third, several sensitivity analyses were performed to verify the robustness of the results. Five gut microbes were found to have a potential causality with COVID-19 severity, namely Betaproteobacteria (beta = 0.096, p = 0.034), Christensenellaceae (beta = -0.092, p = 0.023), Adlercreutzia (beta = 0.072, p = 0.048), Coprococcus 1 (beta = 0.089, p = 0.032), Eisenbergiella (beta = 0.064, p = 0.024). Seven gut microbes were found to have a potential causality with COVID-19 hospitalization, namely Victivallaceae (beta = 0.037, p = 0.028), Actinomyces (beta = 0.047, p = 0.046), Coprococcus 2 (beta = -0.061, p = 0.031), Dorea (beta = 0.067, p = 0.016), Peptococcus (beta = -0.035, p = 0.049), Rikenellaceae RC9 gut group (beta = 0.034, p = 0.018), and Proteobacteria (beta = -0.069, p = 0.035). Two gut microbes were found to have a potential causality with COVID-19 susceptibility, namely Holdemanella (beta = -0.024, p = 0.023) and Lachnospiraceae FCS020 group (beta = 0.026, p = 0.027). Multi-omics mediation analyses indicate that numerous plasma proteins, metabolites, and immune factors are critical mediators linking gut microbiota with COVID-19 outcomes. Sensitivity analysis suggested no significant heterogeneity or pleiotropy. These findings revealed the causal correlation and potential mechanism between gut microbiota and COVID-19 outcomes, which may improve our understanding of the gut-lung axis in the etiology and pathology of COVID-19 in the future.

Large-scale genome-wide association study to identify causal relationships and potential mediators between education and autoimmune diseases.

Objectives: Epidemiological studies suggested a potential connection between education and autoimmune disorders. This study investigated the possible cause-and-effect relationship using a Mendelian randomization approach. Methods: We explored the causality between four education traits (n = 257,841~1,131,881) and 22 autoimmune diseases. The mediating role of smoking (632,802 individuals), BMI (681,275 individuals), alcohol (335,394 individuals), and income (397,751 individuals) was also investigated. Transcriptome-wide association study (TWAS) and enriched signaling pathways analysis were used to investigate the underlying biological mechanisms. Results: Especially, higher cognitive performance was protective for psoriasis (odds ratio (OR) = 0.69, 95% confidence interval (CI) = 0.60-0.79, p = 6.12×10-8), rheumatoid arthritis (RA) (OR = 0.75, 95% CI = 0.67-0.83, p = 4.62×10-6), and hypothyroidism (OR = 0.83, 95% CI = 0.77-0.90, p = 9.82×10-6). Higher levels of educational attainment decreased risks of psoriasis (OR = 0.61, 95% CI = 0.52-0.72, p = 1.12×10-9), RA (OR = 0.68, 95% CI = 0.59-0.79, p = 1.56×10-7), and hypothyroidism (OR = 0.80, 95% CI = 0.72-0.88, p = 5.00×10-6). The completion of highest-level math class genetically downregulates the incidence of psoriasis (OR = 0.66, 95% CI = 0.58-0.76, p = 2.47×10-9), RA (OR = 0.71, 95% CI = 0.63-0.81, p = 5.28×10-8), and hypothyroidism (OR = 0.85, 95% CI = 0.79-0.92, p = 8.88×10-5). Higher self-reported math ability showed protective effects on Crohn's disease (CD) (OR = 0.67, 95% CI = 0.55-0.81, p = 4.96×10-5), RA (OR = 0.76, 95% CI = 0.67-0.87, p = 5.21×10-5), and psoriasis (OR = 0.76, 95% CI = 0.65-0.88, p = 4.08×10-4). Protein modification and localization, response to arsenic-containing substances may participate in the genetic association of cognitive performance on UC, RA, psoriasis, and hypothyroidism. According to mediation analyses, BMI, smoking, and income served as significant mediators in the causal connection between educational traits and autoimmune diseases. Conclusion: Higher levels of education-related factors have a protective effect on the risk of several autoimmune disorders. Reducing smoking and BMI and promoting income equality can mitigate health risks associated with low education levels.