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

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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.