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

COVID-19大流行是现代最大的医疗保健挑战之一。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的日常临床护理中发挥重要作用。然而，COVID-19的异质表现的原因只是不完全了解。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经确定了常见和罕见的宿主变异，有助于其病因学的研究，申请人提供了德国的贡献。然而，尽管在研究COVID-19遗传结构的第一阶段需要收集尽可能多的数据集，但这是以表型不完整和病例定义极不一致为代价的。国家流行病队列网络（NAPKON）是一个全国性的COVID-19队列，在整个医疗保健部门招募，是新成立的德国Netzwerk Universitätsmedizin （NUM）的一部分。NAPKON是世界上最大、最具特征的前瞻性队列之一，目前有5000名参与者可获得深入的纵向临床和分子数据。为了阐明完整的遗传结构，需要对整个等位基因谱的变异进行评估。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，弥合已确定的风险变异、COVID-19的不同表现和潜在病理生理学之间的差距至关重要，这对于制定精确的风险和管理策略以及新的治疗途径至关重要。在这个项目中，我们将(a)生成3800名NAPKON参与者的高质量WES数据集。该数据集将通过温室气体局提供，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担以及多基因风险评分分析确定COVID-19的宿主遗传因素、其后遗症和相关特征，并根据深层表型数据分层进行分组。最后，我们将(c)使用多组学数据对整个等位基因谱的风险变异进行功能性解释。目前的项目为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，通过生成德国任何类型的少数高度可见和可重复使用的大规模WES数据集之一。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内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.