Is genetic chronotype linked to susceptibility to acute Covid-19 infection?

Genomics England Research Registry ID: 430

Registered: 19/08/2020

Expert Summary

The circadian clock plays a critical role in human immune system homeostasis, with immune responses mediated time dependently. The role of the circadian clock in governing immune responses to communicable diseases is rapidly becoming established (Mazzoccoli et al., 2020; Zhuang et al., 2017), with circadian rhythm modulation characterised for both influenza related lung inflammation and survival due to time of original infection (Sengupta et al., 2019). The severity of acute influenza infections is governed by the circadian clock as disruption leads to increased influenza viral replication and transmission (Edgar et al., 2016). Better survival of influenza infection is associated with the time dependent gating of the quantity of NK and NKT cells and inflammatory monocytes in the lungs (Sengupta et al., 2019). Without genetic information patients can be split into circadian chronotype categories, based upon their sleep time phenotypes. These phenotypes are routinely used to find associations between the circadian clock and physiology. Increased inflammation to communicable infections such as influenza have been shown to be correlated with evening chronotypes (Punder et al 2019).
Locally and nationally a number of covid-19 patients have reported insomnia and excessive daytime sleepiness symptoms following coronavirus infection. Based on the current severity of community infection rates covid-19 is thought to be a seasonal respiratory virus (Sajadi et al., 2020). The genes and chronotypes influencing the human immune response show not only circadian gating, but also seasonal expression (Dopico et al., 2015). Chronotypes have been shown to be associated with seasonal changes in health responses (Didikoglu et al., 2020), and this is further affected by perinatal circadian entrainment. Coupled with the excessive UK deaths from individuals born outside the UK this indicates that the immune response to covid-19 may be influenced by both daily and seasonal regulators of immunity. Thus, there may be indications of a biological drive to time of day and seasonal immunity for covid-19 severity.
We will perform an analysis loci in the Genomics England COVID-19 patient cohort to look for association of chronotype with severity of symptoms, using the 351 chronotype markers currently known (Jones et al., 2019) to underly morningness.
Colleagues in Germany are currently running the global chrono corona survey (https://survey.sogosurvey.com/survey.aspx?k=RQsQWRPWXsSVsPsPsP&lang=0&data=) for collecting sleep and phenotypic chronotype information from both affected and unaffected patients to assess the sleep symptoms induced by coronavirus and those resulting from social changes due to lockdown.
The genetic chronotyping data from the Genomics England cohort will allow for a more comprehensive picture of the contribution of chronotype to COVID-19 disease progression and susceptibility, and will give the potential to identify individuals most susceptible from seasonal outbreaks of covid-19 and the possibility of time dependent social distancing.
References
de Punder K, Heim C, Entringer S. Association between chronotype and body mass index: The role of C-reactive protein and the cortisol response to stress. Psychoneuroendocrinology. 2019;109:104388. doi:10.1016/j.psyneuen.2019.104388
Didikoglu A, Canal MM, Pendleton N, Payton A. Seasonality and season of birth effect in the UK Biobank cohort [published online ahead of print, 2020 Mar 28]. Am J Hum Biol. 2020;e23417. doi:10.1002/ajhb.23417
Dopico XC, Evangelou M, Ferreira RC, et al. Widespread seasonal gene expression reveals annual differences in human immunity and physiology. Nat Commun. 2015;6:7000. Published 2015 May 12. doi:10.1038/ncomms8000
Edgar RS, Stangherlin A, Nagy AD, et al. Cell autonomous regulation of herpes and influenza virus infection by the circadian clock. Proc Natl Acad Sci U S A. 2016;113(36):10085-10090. doi:10.1073/pnas.1601895113
Jones SE, Lane JM, Wood AR, et al. Genome-wide association analyses of chronotype in 697,828 individuals provides insights into circadian rhythms. Nat Commun. 2019;10(1):343. Published 2019 Jan 29. doi:10.1038/s41467-018-08259-7
Mazzoccoli G, Vinciguerra M, Carbone A, Relógio A. The Circadian Clock, the Immune System, and Viral Infections: The Intricate Relationship Between Biological Time and Host-Virus Interaction. Pathogens. 2020;9(2):83. Published 2020 Jan 27. doi:10.3390/pathogens9020083
Sajadi MM, Habibzadeh P, Vintzileos A, Shokouhi S, Miralles-Wilhelm F, Amoroso A. Temperature, Humidity, and Latitude Analysis to Estimate Potential Spread and Seasonality of Coronavirus Disease 2019 (COVID-19). JAMA Netw Open. 2020;3(6):e2011834. doi:10.1001/jamanetworkopen.2020.11834
Sengupta S, Tang SY, Devine JC, et al. Circadian control of lung inflammation in influenza infection. Nat Commun. 2019;10(1):4107. Published 2019 Sep 11. doi:10.1038/s41467-019-11400-9
Zhuang X, Rambhatla SB, Lai AG, McKeating JA. Interplay between circadian clock and viral infection. J Mol Med (Berl). 2017;95(12):1283-1289. doi:10.1007/s00109-017-1592-7

Lay Summary

The human daily biological or circadian clock influences many aspects of health and disease including functions of the human immune system. Recent discoveries have shown that respiratory illnesses cause greater infections and inflammation in the evening. People see the effect of the circadian clock in their every day lives often through their chronotype. Many people are familiar with the terms “morning lark” and “night owl”. These descriptions of our sleep patterns can be quantified into chronotypes, which are known to be heritable and have a genetic basis. The detailed genotyping from the 100,000 genomes project allow us to identify associations between chrontoype and diseases. The use of the Covid-19 infection data for the 100,000 genomes participants allows us to use this information in a slightly different way and identify whether morning or evening chronotypes are more likely to have an acute Covid-19 infection. This will allow us to see if night owls or morning larks are more likely to be at risk of Covid-19 infection. This is information on a risk factor that people can estimate based on their own experience of daily life, allowing for easy public dissemination.