Causal relationship between physical activity, leisure sedentary behaviors and COVID-19 risk: a Mendelian randomization study

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has struck humans globally with devastating impacts [1, 2]. The incredible rapid worldwide spread of COVID‐19 prompted the World Health Organization (WHO) to declare COVID‐19 a pandemic on 11 March 2020 [3, 4]. Since SARS-CoV-2 spreads from person to person among those in close contact (within two meters) primarily through respiratory droplets and subsequently causes COVID-19, controlling infectious sources, blocking the transmission routes, and protecting the susceptible population are still the main measures to control its transmission worldwide [5]. Therefore, considering the high contagiousness and serious adverse consequences of COVID-19, identifying behavior-related susceptibility factors of COVID-19 would facilitate effective policies and personalized treatments to control the epidemic spread and save social health care expenditures.

Due to mandatory quarantine requirements, the COVID-19 pandemic has created an environment that reduces habitual physical activity (PA) and promotes excessive time spent in leisure sedentary behaviors (LSB) [6]. Notably, a recent outbreak of highly contagious delta and omicron variants might further exacerbate this problem for a period of time [7]. Observational studies have reported a protective effect of PA on COVID-19 hospitalization [8]. LSB, defined as any awake behavior characterized by an energy expenditure of less than 1.5 metabolic equivalents in a sitting or reclining posture, such as sedentary television watching, computer using and driving [9, 10], have been shown to increase the risk of obesity [11], type 2 diabetes (T2D) [12], cardiovascular disease [13], cancers [14], and overall mortality [15], and to pose a substantial public health burden. Moreover, obesity [16, 17], type 2 diabetes [18, 19] and cardiometabolic disease [20, 21] are well-documented risk factors for severe COVID-19. Thus, we hypothesized that PA might decrease the risk of COVID-19 hospitalization and severity, whereas LSB potentially increases the risk by disrupting metabolic homeostasis. Indeed, recent (small-sample) studies have shown that people who engage in regular physical activity exhibit much lower odds of COVID-19 hospitalization, severe complications and mortality than those who are consistently inactive [22, 23]. However, direct evidence of the causal impact of LSB on COVID-19 susceptibility, severity and hospitalization characteristics remains lacking.

Owing to the inherent defects of conventional designs, existing observational studies are unable to entirely exclude the possibility of reverse causality and confounding factors, which potentially results in biased associations and conclusions [24]. Moreover, randomized controlled studies (RCTs) are unethical and impractical to perform on this topic due to the requirement of significant personnel resources and time-consuming follow-up. Mendelian randomization (MR) is increasingly applied to infer credible causal relationships between risk factors and disease outcomes [25]. Based on the random assortment of genetic variants during meiosis, MR used environmental exposure-related genetic variations as instrumental variables (IVs) to assess the association between exposures (e.g., LSB and PA) and outcomes (e.g., COVID-19 characteristics) [26]. Since genetic variants are randomly assigned at conception prior to disease onset, MR analysis could efficiently preclude confounding factors and identify causal determinants of a certain outcome [27].

Given the uncertainty about the causal association between LSB/PA and COVID-19, in the present study, we applied the MR design to evaluate the potential causal effect of PA/LSB on COVID-19 susceptibility, hospitalization and severity traits using large-scale genome-wide association study (GWAS) data. Overall, this study assesses the impacts of physical restrictions on COVID-19, identifies the susceptible subpopulations with a sedentary lifestyle during the pandemic, and provides constructive suggestions for preventive intervention strategies.

Using large-scale GWAS data from the UK Biobank and the COVID-19 Host Genetics Initiative (HGI), this study implemented multiple MR approaches to appraise the possible causal association of PA/LSB with COVID-19 susceptibility and progression. We demonstrated that accelerometer-assessed PA causally decreased the risk for COVID-19 hospitalization (7%), and leisure television watching causally increased the rate of COVID-19 hospitalization (55%) and severity (85%). In view of the worldwide prevalence of COVID-19, the emergence of new variants and the necessity of isolation measures, our study provides novel insight into reducing the risk of COVID-19 hospitalization and progression by underscoring the necessity of physical activity management during quarantine and stay-at-home mandates.

With the COVID-19 pandemic, people were prone to reduce PA and increase time spent in LSB, due to social distancing restrictions and isolation requirements [22]. However, COVID-19 is a novel and rapidly changing disease caused by SARS-CoV-2 and its variants, the related risk factors for which are even more unclear. Notably, sustained physical inactivity and sedentary behaviors are typically associated with poor physical and mental health and an increased risk of multiple chronic diseases, including obesity, type 2 diabetes, cardiovascular disorders and cancer [11, 12, 14, 15]. A Community-Based Cohort Study in the UK demonstrated that unhealthy behaviors accounted for 51% of the population attributable fraction of severe COVID-19, according to the estimates of risk factor prevalence [23]. Specifically, unhealthy lifestyles of physical inactivity, smoking and obesity were demonstrated to increase the risk of COVID-19 with ORs varying from 1.32 to 2.05 [23]. Despite of these results from small-scale observational studies, direct evidence for the causal relationship between sedentary behaviors and COVID-19 is still lacking [42]. Compared with relatively impractical large-scale prospective clinical trials requiring long-term observation, the MR study sheds a new light on the causal relationship between PA/LSB and COVID in a time- and cost-efficient way.

Intriguingly, leisure television watching causally increased COVID-19 hospitalization and severity rate, which was in accordance with multiple investigations that recognized television watching as the main leisure-time associated sedentary behavior [43]. This result implicated a biological heterogeneity behind domain-specific sedentary behaviors and indicated the importance of distinguishing different sedentary behaviors during COVID-19 management. Compared with other sedentary traits, television watching was the most canonical leisure sedentary behavior that shifted the energy balance toward an energy surplus through fewer breaks, lower energy expenditure and excessive energy (especially snacks) intake [9, 44, 45]. Recent studies illustrated that low energy expenditure manifested by increased BMI was associated with a higher risk of COVID-19 hospitalization and severe complications, including sepsis and respiratory failure [46]. Consistent with these previous findings, our MR analyses clearly indicated a causal association of television watching with COVID-19 hospitalization and severity but not COVID-19 susceptibility. Our results suggested that particular attention should be given to the lifestyle of COVID-19 patients during quarantine. For example, patients should be encouraged to reduce time spent watching television and appropriately increase energy-consuming exercise to improve physical fitness.

Additionally, our in-depth analyses elicited several potential explanations for this causal association between television watching and COVID-19. We first identified several obesity-related phenotypes, including BMI, triglycerides, fasting insulin and T2D, that might play a mediating role linking television watching with COVID-19 incidence. Substantial evidence suggests that obesity and T2D can lead to chronic low-grade inflammation and immune dysregulation, resulting in compromised activation and function of these adaptive immune cells in response to SARS-CoV-2 [47]. Zhang et al. reported that elevated total cholesterol and ApoB levels might increase the risk of COVID-19 infection using MR analyses. Similar to these findings, our results further implied that elevated triglyceride levels should also be monitored in COVID-19 patients [48]. In addition, previous research showed that the proportion of current smokers accumulated with the increase in time spent watching television [45]. Likewise, our study confirmed that increased television watching led to a lower likelihood of smoking cessation among smokers. Given that smoking behavior is a well-established cause of COVID-19, it might serve as a key intermediate factor in the television watching-COVID-19 pathway. Additionally, previous MR studies unveiled a causal association between psychiatric disorders and COVID-19 [49, 50]. Compared with computer use and driving, television watching is a more immersive, less reflective and communicative form of leisure entertainment. Sustained television viewing was consistently accompanied by poor physical and mental health (such as anxiety and depression), which might partially contribute to COVID-19 as well. Finally, elderly people tended to spend more time on watching television as a leisure entertainment, whereas the young population were more likely to use computers or drive. Thus, more attention should be given to elderly people with respect to their physical activity instructions during COVID-19 pandemic social restrictions. Notably, further studies are warranted to determine the exact degree of LSB mediation for COVID-19. Without specific mediation analysis, the direct effect of television watching on COVID-19 could not be determined.

Taken together, our findings supported the hypothesis that LSB (especially television viewing) increases COVID-19 risk, and strategies to enhance physical activity during the COVID-19 pandemic deserve particular attention. First, during the quarantine period for controlling infection sources and cutting off the transmission, residents should be encouraged to appropriately increase their energy consumption behaviors rather than engage in leisure sedentary behaviors. Light-to-moderate-intensity activities, such as housework and brisk walking, should also be encouraged [51]. Moreover, anti-smoking advocacy should be routinely performed among COVID-19 patients, which could be of great significance in delaying the progression of the disease, reduce its severity, and promote early recovery. In addition, as a high-risk group for COVID-19 and major audience for television, individuals with obesity or type 2 diabetes, especially elderly adults, should be assisted in reducing leisure television viewing time and participating in physical activities.

In general, the statistical power of the IVW approach is dramatically higher than that of the other MR approaches, especially MR-Egger [52]. Confidence intervals were calculated from the same equations that generated P values. Therefore, not surprisingly, the MR–Egger results with low statistical power had wider confidence and nonsignificant P values when compared with IVW in the present study. For the same reason, IVW was usually used as the main method to screen for potentially significant results. Sensitivity analyses and other MR methods were implemented to ensure the robustness of IVW estimates. IVW estimates would be biased if horizontal pleiotropy existed. In this scenario, the MR-Egger estimates should be referenced because this method adapts the IVW analysis by allowing the horizontal pleiotropic effect across all SNPs to be unbalanced or directional [53]. In most MR analyses, researchers have strengthened the requirement for consistent beta direction in all MR approaches, which was also used in our study [54, 55].

However, several limitations should be taken into account in our study. First, since this study was conducted among European ancestry participants, the results cannot be immediately generalized to other ethnic groups with different lifestyles and cultural backgrounds. Second, since MR analyses extrapolated causal hypotheses by exploiting the random allocation of genetic variants, it was difficult to completely distinguish between mediation and pleiotropy using MR approaches. The generous variants in our genome probably affect one or more phenotypes. Third, there was a lack of additional mediator analysis and observation studies to further confirm the metabolic mechanisms involved in the causal relationship between television watching and COVID-19. Due to the limitations of the UK Biobank data, future studies are required to confirm the causality and explore potential mechanisms, which is indispensable for developing relevant clinical recommendations.

In conclusion, leveraging large-scale genetic summary data, our study first strengthened the evidence that PA/LSB was causally associated with the hospitalization and severity of COVID-19. Further work is warranted to decipher the underlying mechanisms linking leisure television watching with COVID-19. Given the COVID-19 pandemic and the necessity of social quarantine, intensive attention should be given to lifestyle management, such as reducing leisure sedentary behaviors and encouraging proper exercise, to combat COVID-19.