Genetic causal correlations between allergic diseases and COVID-19: A systematic two-sample and bidirectional MR studyWord count: 597To the Editor,Allergic diseases (ADs) such as asthma are presumed risk factors for COVID-19 infection with greater severity.1 However, recent observational studies suggest that the assumed correlation remains controversial.2 We aimed to answer the following questions: (1) Are there causal correlations between various ADs and COVID-19 infection/severity? (2) If so, how do they affect each other?We employed a two-sample, bidirectional Mendelian randomization (MR) analysis to systematically explore genetic correlations between ADs and COVID-19 infection/severity.3 The primary MR analyses contained three successive parts. First, we treated each COVID-19 phenotype (18,152 critically ill cases, A2; 44,986 hospitalized cases, B2; 159,840 reported infection cases, C2) as exposure and each AD (broad allergic disease (BAD), asthma, allergic dermatitis (ADE), shrimp allergy (SA) and peach allergy (PA)) as outcome to evaluate whether the COVID-19 outbreak would genetically affect the incidence rates of ADs (Fig. S1A and S1C ). Conversely, we considered each type of AD as an exposure and COVID-19 phenotypes as outcomes to identify genetic risk factors for COVID-19 infection/severity (Fig. S1B and S1C ). Secondly, we employed two available independent GWAS datasets (Asthma2018 and ADE2021) to further validate those significant correlations (Fig. S1D ). Finally, we investigated the mechanisms underlying the significant correlations based on well-known theories of pathogenesis for COVID-19 or ADs (Fig. S1E ). After multiple pre-processing steps, we applied the most suitable MR approach upon different scenarios, and thus a p-value <0.05 was considered statistically significant. Details are presented in supporting information (SI ) and Table S1 (TS1) .Our MR results consistently indicated that all COVID-19 phenotypes were causally associated with an increased asthma prevalence (OR>4.21, p <1.30×10-78) (Table 1 ). Validation results from Asthma2018 further confirmed the causal correlation of critically ill with asthma using two different MR methods (both OR=1.05,p <4.19×10-2) (SI-TS2 ). Both critically ill and hospitalized cases were causally associated with a decreased prevalence of ADE (OR<0.93,p <2.65×10-2) (Table 1 ), although it did not obtain further validation. Interestingly, hospitalized cases showed a significant association with an increased rate of PA (OR=2.95, p =3.86×10-2) (Table 1 ).MR analyses found that asthma was a causally protective factor for hospitalized cases (OR=0.9975, p =4.28×10-2;Table 2 ), which was confirmed by another GWAS dataset (Asthma2018) upon adopting multiple MR methods (OR=0.87-0.98,p <5.61×10-3) (SI-TS2 ). Besides, the MR analyses implied that SA was also a risk factor for the COVID-19 infection/severity (OR>1.04,p <6.73×10-3) (Table 2 ).In the investigation of underlying molecular mechanisms, MR analyses indicated that COVID-19 phenotypes, especially severe symptoms, were causally correlated to hematological traits (HT and MCH) and immune-related cell counts (including LYMPH and CD3+ T, CD56+ NK, and CD8+ T cell counts), implying that a cytokine storm induced by COVID-19 infection/severity may cause a substantial damage to host immune response and further induce various ADs (SI-TS3 ).4 In turn, MR analyses for causal effects of ADs on ACE2 protein expression in peripheral blood suggested that asthma was causally correlated with a decreased ACE2 protein expression with two different methods (SI-TS4, both OR=0.9997,p =4.30×10-2), while SA with a marginally increased protein expression (OR>1.01,p <8.90×10-2) (SI-TS4 ). These findings partially explained that ADs such as asthma and SA may have causal effects on COVID-19 infection/severity by affecting ACE2 protein expression, which directly exerts a biological function in peripheral blood tissue.5 Several previous studies also suggested that allergic sensitization in asthma patients was associated with a low ACE2 expression in respiratory tracts.6In conclusion, our MR analyses suggest a bidirectional causal effect between COVID-19 phenotypes and ADs, especially asthma. The underlying molecular mechanisms of the causal effects may be beneficial in developing effective therapeutic strategies for allergic patients with COVID-19 infection and for long-term COVID-19 symptoms physical characteristics should be prioritized.