Long COVID as a putative subtype of chronic fatigue syndrome

摘要 SARS-CoV-2感染的一个标志是个体健康反应的不可预测的变化， 从无症状到患有危及生命和难治性呼吸道疾病的人，最后是长期 持续的症状，这里定义为长期COVID。长期新冠病毒的核心症状非常像慢性病 疲劳综合征（CFS）伴多系统主诉，包括衰弱性疲劳、心率波动和 头痛.在CFS中，感染性触发因素被怀疑但未被证实，并且通常在流感样 症状由于疾病机制尚不清楚，目前的治疗选择是对症的。 0.2-0.4%的人口患有CFS。这项提案的目的是阐明生物学 长期COVID的机制和风险因素，并检验长期COVID是慢性 疲劳综合症为了阐明潜在的机制，我们将使用来自三个不同生物库的数据， 我们已经建立了COVID遗传学工作组，并通过CFS联盟。在目标1中，我们将检查遗传 通过由46个队列和超过150万人组成的长期COVID工作组， 个体此外，我们将对三个生物库（N = 740，000）的CFS进行荟萃分析。该分析 将阐明CFS和Long COVID之间的联系，并确定这两种疾病的风险变体。在Aim中 2，我们将探索免疫分子的贡献，微调对病原体的反应。免疫 防御依赖于特定的细胞来防止感染或破坏病毒和细菌病原体以及身体自身的病原体 被感染的细胞。这一目标将检查保护免受感染、COVID-19或 合并症易患长期新冠我们将特别关注那些具有很大解释力的区域， 人类白细胞抗原（HLA）除了探索全基因组的关联外， 建立了COVID-19基因座。这一目标将揭示哪些免疫特征会增加风险或保护免受长期COVID的影响 和CFS，阐明了导致疾病发展的免疫反应类型。在目标3中，我们 估计遗传性和共享遗传与环境风险。我们将估计环境的比例 通过对兄弟姐妹、双胞胎和一般人群的分析，了解CFS和长期COVID背后的遗传因素 在FinnGen和英国生物银行。这一目标将风险贡献与环境风险和遗传学区分开来， 共享环境的背景提供了对共享环境与遗传优势的深入了解 疾病发展所需的因素。拟议的工作阐明了风险因素和合并症 导致CFS和长期COVID的因素，包括可能共有的疾病病因学、病原学和 科摩罗。该项目为未来疾病治疗提供生物学见解，并促进早期疾病 诊断.

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.