key: cord-0892711-ww234t5i authors: Zhang, X.; Wang, B.; Liu, D.; Zhang, J.; Tian, Q.; Meng, X.; Hou, H.; Song, M.; Wang, W.; Wang, Y. title: Causal associations between COVID-19 and Atrial Fibrillation: A bidirectional Mendelian randomization study date: 2020-08-14 journal: nan DOI: 10.1101/2020.08.13.20174417 sha: 0c3a4702bd525e80fb3a00db518f7f004aa1d692 doc_id: 892711 cord_uid: ww234t5i Abstract Background Observational studies showed that coronavirus disease 2019 (COVID-19) attacks universally and its most menacing progression uniquely endangers the elderly with cardiovascular disease (CVD). Whether COVID-19 is causally related to increasing susceptibility and severity of atrial fibrillation (AF), the main form of CVD, remains still unknown. Methods The study aims to investigate the bidirectional causal relations of COVID-19 with AF using two-sample Mendelian randomization (MR) analysis. Results MR evidence suggested genetically predicted severe COVID-19 was significantly associated with higher risk of AF (odds ratio [OR], 1.041; 95% confidence interval (CI), 1.007-1.076; P = 0.017), while genetically predicted AF was not causally associated with severe COVID-19 (OR, 0.831; 95% CI, 1.619-1.115; P=0.217). There was limited evidence to support association of genetically proxied COVID-19 with risk of AF (OR, 1.051; 95% CI, 0.991-1.114; P=0.097), and vice versa (OR, 0.163; 95% CI, 0.004-6.790; P=0.341). MR-Egger indicated no evidence of pleiotropic bias. Conclusion Overall, severe COVID-19 may causally affect AF through independent biological pathway. Survivors from severe COVID-19 might be of high risk of AF in the future. Key words Coronavirus disease 2019; Atrial Fibrillation; Bidirectional mendelian randomization Coronavirus disease , which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-COV2) and represents the causative agent of a potentially fatal disease, rapidly emerged as a global pandemic and afflicted global finances and healthcare systems severely 1 . The virus attacks universally and is vulnerable to the elderly, especially those with cardiovascular comorbidities such as diabetes mellitus, hypertension, heart failure, and coronary heart disease 2 . COVID-19 may cause adverse impact on the heart and cardiovascular system. Recent studies have found that SARS-COV2 infection may damage cardiac myocytes and increase atrial fibrillation (AF) risk [3] [4] [5] . However, those findings are still susceptible to confounding and reverse causation that cannot be fully ruled out in observational studies. Mendelian randomization (MR) is a burgeoning field that utilizes genetic variants that are robustly associated with such modifiable exposures to generate more reliable evidence 6 . This approach relies on the natural, random assortment of genetic variants during meiosis yielding a random distribution of genetic variants 7 . Genome-wide association studies (GWAS) data, which typically provide regression coefficients summarizing the associations of many genetic variants with various traits, are potentially a powerful source of data for MR analysis 8 . Therefore, we performed bidirectional MR analyses for causal inference between COVID-19 and AF using summary statistics GWAS results of COVID-19 and AF. Understanding the 4 bidirectional relations between COVID-19 and AF is of significant public health importance about disease prevention and management of complications. Summary genetic association estimates for risk of COVID-19 were obtained from the most recent version of GWAS analyses of the COVID- 19 We only retained independent variants from each other based on European ancestry reference data from the 1000 Genomes Project (Linkage disequilibrium [LD], r 2 threshold = 0.0001). In the main analyses, we combined MR estimates for each direction of potential influence using inverse variance-weighted (IVW) meta-analysis, which actually was a weighted regression of SNP-outcome effects on SNP-exposure effects (the intercept is constrained to 0) 8 We conducted MR-Egger analysis which allows the intercept to be freely assessed as an indicator of average pleiotropic bias 11 . In order to assess robustness of significant results, we applied further tests for horizontal pleiotropy to detect heterogeneous outcomes, including leave one out analysis, the Cochran Q statistic, and the MR Egger intercept test of deviation from the null 14 . Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs) of outcomes per genetically predicted increase in each exposure factor. For bidirectional MR analyses, the causal relationships between COVID-19 and AF were delineated into four potential parts. Figure 1 showed an overview of the bidirectional MR study to investigate these explanations. If the P value was less than 0.05 only in forward MR for Explanation 1, there was significant association of genetically instrumented COVID-19 with higher AF risk. Then we conducted the reverse MR analysis assessing whether AF affected COVID-19. This reverse causal 7 association was existed if P value was less than 0.05 in Explanation 2. The Explanation 3 showed there were bidirectionally causal associations between COVID-19 and AF (P <0.05). There was no any causal association in forward and reverse MR (P >0.05) as showed in Explanation 4. All data analyses for MR were conducted by "twosampleMR" and "MR-PRESSO" packages in the R environment (R version 3.6.3, R Project for Statistical Computing). This package harmonizes exposure and outcome data sets including information on SNPs, alleles, effect sizes, standard errors, P values, and effect allele frequencies for selected exposure instruments. The summary genetic associations data were reported in the Supplement (Figure 2A and 2B). For IVs, MR-PRESSO did not detect any potential outliers. Associations between each variant with severe COVID-19 and risk of AF was displayed in Figure 3 . The summary genetic associations data of AF were reported in the Supplement Table 2 . As shown in Table 1 COVID-19 was not substantially driven by any individual SNP ( Figure 2D ), while the association between genetically instrumented AF with COVID-19 was driven by rs17042121 ( Figure 2C ). To our knowledge, this is the first study to investigate the causal relationship between COVID-19 and AF using a bidirectional MR. Our study showed that severe COVID-19 may causally affect AF through independent pathway. Our study found that severe COVID-19 was causally associated with the risk of AF, indicating that the incidence of AF in patients with COVID-19 corresponds to the severity of illness. The finding was supported by the observational epidemiology study, which found that cardiac arrests and arrhythmias were more likely to occur in the more severe patients 3 . A worldwide cross-sectional study researched the cardiac arrhythmic in hospitalized COVID-19 patients including severe COVID-19 found that atrial fibrillation was the most common cardiac arrhythmia noted in these patients 15 . Arrhythmia included atrial fibrillation was observed in 7% of patients who did not necessitate ICU treatment and in 44% of subjects who were admitted to an ICU 16 In our analysis, we did not find any associations between AF and COVID-19 or severe COVID-19. However, it is not clear whether AF would contribute to increasing the risk for severe forms of COVID-19, worse prognosis, or even higher mortality. The limitations of the current study should be addressed. First, due to the limitation of data resource, stratified analyses or analyses adjusted for other covariates were impossible. In addition, it is hard to represent the universal conclusions for other ethnic groups based on European population. In conclusion, our study showed that AF might be a consequence rather than a risk factor of severe COVID-19, indicating that the future study should pay attention to the prognosis of severe COVID-19. All data generated or analyzed during this study are included in this published article and its supplementary information files. All authors have approved the manuscript and its submission. No potential conflicts of interest were disclosed by the authors. The study was supported by grants from the China-Australian Collaborative Grant (NSFC 81561128020-NHMRC APP1112767). We want to acknowledge the participants and investigators of the FinnGen study. We thank the COVID-19 host genetics initiative in UK Biobank and severe COVID-19 GWAS Group investigators for making the summary GWAS results publicly accessible. The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. An interactive web-based dashboard to track COVID-19 in real time COVID-19 Illness and Heart Failure: A Missing Link? 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