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.
