Long COVID as a putative subtype of chronic fatigue syndrome

Abstract A hallmark of infection with SARS-CoV-2 is the unpredictable variation in individual health response from those who are asymptomatic to those with life-threatening and refractory respiratory illness, and finally those with long lasting symptoms, here defined as Long COVID. The core symptoms of Long COVID are remarkably like chronic

fatigue syndrome (CFS) with multisystem complaints including debilitating fatigue, fluctuating heart rate and headache. In CFS, an infectious trigger has been suspected but not proven and onset often follows flu-like symptoms. As disease mechanisms are not understood, the treatment options are currently symptomatic.

Between 0.2-0.4% of the population suffer from CFS. The goal of this proposal is to elucidate the biological mechanisms and risk factors for Long COVID and test the hypothesis that Long COVID is a subtype of chronic fatigue syndrome. To elucidate potential mechanisms, we will use data from three different biobanks, a Long

COVID genetics working group we have built and through a CFS consortium. In Aim 1, we will examine genetic risk factors and comorbidities through the Long COVID working group comprising 46 cohorts and over 1.5 million individuals. In addition, we will do a meta-analysis of CFS across three Biobanks (N = 740,000). This analysis

will elucidate the connection between CFS and Long COVID and identify risk variants for both diseases. In Aim 2, we will explore contribution from immune molecules that fine tune response to pathogens. The immune defense relies on specific cells to prevent infection or to destroy viral and bacterial agents and the body's own

infected cells alike. This aim will examine if the genetic variants that protect from infections, COVID-19, or comorbidities, predispose to Long COVID. We will specifically focus on those regions that have large explanatory power such as the human leukocyte antigen (HLA) in addition to exploring associations genome-wide at

established COVID-19 loci. This aim will reveal which immune traits increase risk or protect from Long COVID and CFS, elucidating the type of immune responses responsible for disease development. In Aim 3, we will estimate heritability and shared genetic vs. environmental risk. We will estimate the proportion of environmental

and genetic factors behind CFS and Long COVID through analysis of siblings, twins, and the general population in FinnGen and UK Biobank. This aim distinguishes the risk contribution from environmental risk and genetics in the context of a shared environment providing insight into the strength of shared environmental vs. genetic

factors that are needed for disease development. The proposed work elucidates risk factors and comorbidities that contribute to CFS and Long COVID including the possibly shared disease etiology, symptomatology, and comorbidity. The project provides biological insights for future disease treatment and facilitates early disease

diagnosis.