Exome sequencing in the National Pandemic Cohort Network (NAPKON) to decipher COVID-19 host genetics

COVID-19疫情是现代最大的医疗挑战之一。SARS-CoV-2感染急性和亚急性期的各种表现及其慢性后遗症将在未来几年内在埃塞俄比亚的临床护理中发挥重要作用。然而，COVID-19呈现异质性的原因尚不完全清楚。宿主遗传因素是形成COVID-19临床表型的重要决定因素。大型国家和国际财团已在申请人提供德国贡献的研究中确定了导致其病因的宿主常见和罕见变异。然而，尽管对COVID-19遗传结构的第一阶段研究的特点是需要收集尽可能大的数据集，但这是以不完整的表型和极端异质的病例定义为代价的。国家大流行队列网络（NAPKON）是一个全国性的COVID-19队列，在整个医疗保健行业招募，并作为新成立的德国Netzwerk Universitätsmedizin（NUM）的一部分建立。目前有超过5,000名参与者可获得深度纵向临床和分子数据，NAPKON是全球最大和最具特征的前瞻性队列之一。为了阐明完整的遗传结构，需要评估来自整个等位基因谱的变体。因此，全外显子组测序（WES）对于充分利用所创建的广泛分子数据集并弥合已识别的风险变体、COVID-19的不同表现和潜在病理生理学之间的差距至关重要，这是精确风险和管理策略以及新治疗途径的关键。在这个项目中，我们将（a）生成一个由3,800名NAPKON参与者组成的高质量WES数据集。该数据集将通过GHGA提供，作为所有类型COVID-19研究的国家开放获取资源。然后，我们将（B）通过单变异关联和基因负荷以及多基因风险评分分析，确定COVID-19的宿主遗传因素、其后遗症和相关性状，这些分析将在基于深度表型数据分层的组中进行。最后，我们将（c）使用多组学数据从整个等位基因谱中功能性地筛选出具有高风险的变体。本项目通过生成德国为数不多的任何类型的高度可见和可重复使用的大型WES数据集之一，为NAPKON/NUM的努力，基因组学领域和整个研究界提供了独特的附加值。同样重要的是，该项目旨在扩大德国尚未充分研究的宿主遗传学领域。最后，该数据集将提高德国基因组学研究在国家和国际层面的知名度，促进德国参与未来世界级的全球合作研究。

The COVID-19 pandemic represents one of the largest healthcare challenges in modern times. The various manifestations during the acute and subacute phases of SARS-CoV-2 infections as well as their chronic sequelae will play a significant role in quotidian clinical care for years to come. Yet, the reasons for the heterogeneous presentations of COVID-19 are only incompletely understood. Host genetic factors present important determinants shaping the clinical phenotype of COVID-19. Large national and international consortia have identified both common and rare variants of the host contributing to its etiology in studies to which the applicants provided the German contributions. However, while the first phase of studies into the genetic architecture of COVID-19 was marked by the need to collect the largest datasets possible, this came at the cost of incomplete phenotyping and extremely heterogeneous case definitions. The National Pandemic Cohort Net (NAPKON) is a nationwide COVID-19 cohort recruited across the entire healthcare sector and was established as part of the newly founded German Netzwerk Universitätsmedizin (NUM). With currently >5,000 participants for whom deep longitudinal clinical and molecular data are available, NAPKON is one of the largest and best characterized prospective cohorts worldwide. To elucidate the complete genetic architecture, variants from the entire allelic spectrum will need to be assessed. Whole exome sequencing (WES), therefore, is vital to fully capitalize on the extensive molecular dataset created and to bridge the gap between the identified risk variants, the different manifestations of COVID-19 and the underlying pathophysiology, which is key to precise risk and management strategies as well as novel treatment avenues. In this project we will (a) generate a high-quality WES dataset of 3,800 NAPKON participants. This dataset will be made available via GHGA as a national, open access resource for all types of COVID-19 research. We will then (b) identify host genetic factors for COVID-19, its sequelae and associated traits by single variant association and gene burden as well as polygenic risk score analyses, to be performed in groups stratified based on deep phenotypic data. Finally, we will (c) use multiomics data to functional interprete risk variants from the entire allelic spectrum. The present project provides unique added value for the NAPKON/NUM efforts, the field of genomics and the research community as a whole by generating one of few highly visible and reusable large-scale WES datasets of any kind in Germany. Of equal importance, this project seeks to expand the yet understudied field of host genetics in Germany. Finally, this dataset will increase the visibility of German genomics research at national and international levels, fostering German participation in future world-class collaborative global research.