Genetic and phenotypic analysis of the causal relationship between aging and COVID-19

Abstract

Background 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. Methods 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. Results We 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. Conclusions Our 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.

Identifying factors contributing to increased susceptibility to COVID-19 risk: a systematic review of Mendelian randomization studies

“…82 Another study that was published in a peer-reviewed journal showed accelerated ageing was associated with higher COVID-19 risk, although the publication was not indexed in PubMed. 102 However, there were methodological concerns in some studies, such as interpreting liability as the effect of disease diagnosis, 87 the lack of comprehensive assessment of IV assumptions 96 and insufficient details for replication. 100 …”

Biological age is increased by stress and restored upon recovery

“…36 Not only are the elderly up to 90-fold more vulnerable to death from COVID-19, 37 but we and others have previously reported that accelerated biological age is associated with incidence and severity of COVID-19. [38][39][40][41][42] Longitudinal biological age data covering the COVID-19 disease course is also extremely limited.…”

SARS-CoV-2 and EBV; the cost of a second mitochondrial “whammy”?

“…The likelihood of this happening could be increased in people who already have sub-optimal mitochondrial function associated with a sedentary lifestyle. In this regard, a genetic and phenotypic analysis of the causal relationship between ageing and COVID-19 seems to indicate that accelerated biological ageing is a key factor in susceptibility risk, with both altered Notch signalling and B cell functioning being important [ 19 ].…”