Phenome-wide Association Study To Explore The Long-term Symptoms After Infection With COVID-19

Background:As the pandemic of coronavirus disease 2019(COVID-19)persists,many studies in China and abroad have found that patients with COVID-19 develop cardiovascular,neurological/psychiatric,and endocrine symptoms after the acute infection period.The World Health Organization has defined this condition as the post-COVID-19 condition.Most of the current post-COVID-19 condition studies are observational designs,and the association effects are susceptible to confounding factors that may lead to biased estimates.In addition,because COVID-19 is a kind of emerging infectious disease,the observation period is short,and some unknown and potential sequelae symptoms have not yet been revealed.The above-mentioned factors contributed to the high heterogeneity of results,low level of evidence,and limited outcome information in studies related to post-COVID-19 condition.Phenome-wide association analyses(PheWAS)is a method that explores the association between all phenotypes and a given exposure within the context of a phenome-wide group.This hypothesis-free approach helps to identify new associations across the human phenome,thus mapping the association effects of exposure on the entire human phenome and providing clues for a comprehensive understanding of disease mechanisms.In addition,to further explore causal effects,Mendelian randomization(MR)is commonly used to validate statistically significant exposure→outcome association effects from the PheWAS test(this research strategy has been applied in non-communicable diseases(NCDs).Due to differences in host genetic susceptibility,humans can develop different disease phenotypes upon infection with pathogens.Several genome-wide association studies(GWAS)related to COVID-19 have been publicly reported,providing summary-level data to support our study.Therefore,in this study,we used the previous approach to explore NCDs(PheWAS combined with MR analysis strategy)to systematically and comprehensively explore the symptoms of COVID-19 and to provide a scientific basis for elucidating the long-term symptoms of COVID-19.Methods:1.PheWAS study:GWAS summary data were obtained from the 7th edition of the COVID-19 Host Genetics Program and electronic health data from the UK Biobank(UKB).In this study,a polygenic risk score(PRS)for COVID-19 was constructed as the exposure,and a human full phenotype database was constructed as the outcome.The PheWAS analysis based on individual data is essentially a regression analysis,so logistic regression was used for the analysis.In addition,this study used the False discovery rate(FDR)method for multiple corrections of P-values to control for Type Ⅰ error probability,and when P<0.05 was considered as a potentially statistically significant result,it was considered as a robust result by FDR correction.2.Univariate MR:Inverse-variance weighted(IVW)method was used as the main analysis method,and the simple median method,weighted median method,MR-Egger regression method,and Mendelian randomized multi-effect residuals and outliers method were used as sensitivity methods.Multiple univariate MR methods were used to further validate the statistically significant exposure→outcome association effects obtained from the PheWAS test and to provide robust causal evidence for the association between COVID-19 and related human disease phenotypes.3.Multivariate Mendelian randomization(MVMR):The MVMR method was used to test whether the association effects were confounded by potential covariates such as smoking,alcohol consumption,and body mass index(BMI),yielding more robust causal evidence.Results:1.Results of PheWAS analysis:general type COVID-19 resulted in the greatest number of diseases with an elevated risk of morbidity,with 51 diseases in 13 systems,of which cardiovascular,oncological,and endocrine/metabolic systems were particularly significant.Hospitalized COVID-19 and critically ill COVID-19 caused an increased risk of 36 diseases(13 systems)and 35 diseases(15 systems),respectively(P<0.05).2.Univariate MR test results:IVW test results showed that critical,hospitalized,and general COVID-19 adversely affected 21,18,and 36 diseases,respectively(P<0.05),mainly in the cardiovascular,cancer,neuropsychiatric,and cutaneous systems.After the remaining univariate MR method and other sensitivity analysis methods were tested,the more robust results were:critical COVID-19 and hyperlipidemia,breast malignancy(HER2 negative),ovarian cancer and esophageal cancer;hospitalized COVID-19 and atrioventricular block,hyperlipidemia,mixed disorders of control over disease,behavior,and emotion;general COVID-19 and coronary artery cardiac disease,intestinal diverticular disease,hypothyroidism,Paget’s disease,and emotionally unstable personality disorders.3.MVMR test results:the effect values of critical COVID-19 were increased for non-toxic diffuse goiter,thyrotoxicosis with diffuse goiter,and breast malignancy(HER2 negative)compared to univariate MR.The effect of hospitalized COVID-19 for breast malignancy(HERpositive)and breast malignancy(HER2-negative)increased in univariate MR analysis,while the effect with gastroesophageal reflux disease(GERD)decreased after correction for covariates.The hazard effect of COVID-19 for ischemic stroke(large atherosclerotic),mucinous ovarian cancer with low malignancy,breast malignancy(HER positive),father’s history of Alzheimer’s disease,and childhood anhedonic epilepsy was increased compared to univariate MR analysis,whereas the effect with duodenal ulcer was decreased compared to univariate MR method.Conclusions:Based on large-scale GWAS summary data and electronic health data,this study identified that COVID-19 can cause harmful effects on all human systems,especially the association effects of general COVID-19 with cardiovascular,oncological,and endocrine/metabolic systems were more significant.In addition,critical,hospitalized,and general COVID-19 all have potentially harmful effects on breast malignancies.This study provides an important scientific basis for a further comprehensive understanding of the harmful effects of post-CO VID-19 condition and the development of preventive and curative measures.