Long COVID as a putative subtype of chronic fatigue syndrome

摘要 感染SARS-CoV-2的一个标志是个人健康反应的不可预测的变化 那些患有危及生命和难治性呼吸道疾病的人没有症状，最后是那些长期 持续性症状，在这里定义为慢性冠状病毒病。慢性COVID的核心症状非常类似于慢性 疲劳综合征(CFS)有多系统主诉，包括虚弱的疲劳、心率波动和 头疼。在CFS中，传染性触发因素被怀疑但尚未得到证实，发病通常伴随着流感样症状 症状。由于疾病机制尚不清楚，目前的治疗选择是有症状的。 0.2%-0.4%的人口患有慢性疲劳综合征。这项提议的目的是阐明生物 慢性冠状病毒感染的发病机制和危险因素，并验证慢性冠状病毒感染亚型的假设 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，一个很长的 我们已经建立并通过CFS联盟建立了COVID遗传学工作组。在目标1中，我们将检查基因 风险因素和合并症通过由46个队列和150多万人组成的COVID长期工作组 个人。此外，我们将对三个生物库(N=740,000)的CFS进行元分析。这一分析 将阐明慢性疲劳综合征和慢性冠状病毒病之间的联系，并确定这两种疾病的风险变异。在AIM 2，我们将探索免疫分子对病原体的微调反应的贡献。免疫者 防御依赖于特定的细胞来防止感染或摧毁病毒和细菌以及身体自身 被感染的细胞相似。这一目标将检查保护免受感染的基因变体，新冠肺炎，或 合并症，易患慢性冠状病毒。我们将特别关注那些具有较大解释性的地区 例如人类白细胞抗原(HLA)的力量，除了在全基因组范围内探索相关性之外 建立了新冠肺炎的定位。这一目标将揭示哪些免疫特征会增加风险或防止长期COVID 和CFS，阐明了导致疾病发展的免疫反应的类型。在《目标3》中，我们将 估计遗传力和共同的遗传风险与环境风险。我们将估计环境污染的比例 通过对兄弟姐妹、双胞胎和普通人群的分析，发现CFS和Long COVID背后的遗传因素 在芬兰和英国生物库。这一目的将风险贡献与环境风险和遗传因素区分开来 共享环境的背景提供对共享环境与遗传的优势的洞察 疾病发展所需的因素。拟议的工作阐明了风险因素和共病。 导致慢性疲劳综合征和长期冠状病毒感染，包括可能共同的疾病病因、症状和 合并症。该项目为未来的疾病治疗提供了生物学见解，并促进了早期疾病的发生。 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.