Abstract
BackgroundEpidemiological studies revealed that the elderly and those with comorbidities are most affected by COVID-19, but it is important to investigate shared genetic mechanisms between COVID-19 risk and aging.MethodsWe conducted a multi-instrument Mendelian Randomization analysis of multiple lifespan-related traits and COVID-19. Aging clock models were applied to the subjects with different COVID-19 conditions in the UK-Biobank cohort. We performed a bivariate genomic scan for age-related COVID-19 and Mendelian Randomization analysis of 389 immune cell traits to investigate their effect on lifespan and COVID-19 risk.ResultsWe show that the genetic variation that supports longer life is significantly associated with the lower risk of COVID-19 infection and hospitalization. The odds ratio is 0.31 (P = 9.7 × 10−6) and 0.46 (P = 3.3 × 10−4), respectively, per additional 10 years of life. We detect an association between biological age acceleration and future incidence and severity of COVID-19 infection. Genetic profiling of age-related COVID-19 infection indicates key contributions of Notch signaling and immune system development. We reveal a negative correlation between the effects of immune cell traits on lifespan and COVID-19 risk. We find that lower B-cell CD19 levels are indicative of an increased risk of COVID-19 and decreased life expectancy, which is further validated by COVID-19 clinical data.ConclusionsOur analysis suggests that the factors that accelerate aging lead to an increased COVID-19 risk and point to the importance of Notch signaling and B cells in both. Interventions that target these factors to reduce biological age may reduce the risk of COVID-19.
Highlights
Epidemiological studies revealed that the elderly and those with comorbidities are most affected by COVID-19, but it is important to investigate shared genetic mechanisms between COVID-19 risk and aging
We investigated four additional traits genetically correlated with lifespan using published case-control studies: Alzheimer’s disease[16], coronary artery disease (CAD)[17], type 2 diabetes[18], and smoking[19] (Table S1)
We applied Mendelian Randomization (MR) using GSMR to test for potential causal associations between four lifespan-related traits and COVID-19, including lifespan, longevity, healthspan, and healthy aging (Table S1)
Summary
We conducted a multi-instrument Mendelian Randomization analysis of multiple lifespan-related traits and COVID-19. Aging clock models were applied to the subjects with different COVID-19 conditions in the UK-Biobank cohort. We performed a bivariate genomic scan for age-related COVID-19 and Mendelian Randomization analysis of 389 immune cell traits to investigate their effect on lifespan and COVID-19 risk. We studied four lifespan-related traits (lifespan, longevity, healthspan, and a combined trait) with publicly available GWAS summary statistics. In the GWAS setting, parental lifespan is the same phenotype as the general lifespan of individuals (but with a weaker power) due to the fact that the genetic effect on a parental phenotype is half of the individual’s phenotype itself. Thanks to the large sample size of UK Biobank, such a GWAS is powerful enough to uncover the genetic architecture[11]
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