REACT-GE: Multi-omics to identify biological pathways underlying severity of SARS-CoV-2 infection.

We know that some people are more at risk from COVID-19 than others, for instance if they are older, from a minority ethnic group or have other health conditions. But one of the biggest COVID-19 puzzles is why some people who are younger or previously fit develop very severe symptoms whilst people like them who are seemingly much more at risk, only get mild illness. One of the answers may lie in the genome, the body's instruction manual, and how it interacts with the environment. These interactions may protect or amplify the response to infection with the virus that causes COVID-19. This project brings together a leading international team of researchers with the expertise across different disciplines essential to be able to understand how the virus interacts with the body and to identify new treatment opportunities. It includes the research group which is responsible for patients that have been severely affected by COVID-19 and admitted to intensive care (GenOMICC) and the organisation that sequences and interprets genomes for the NHS (Genomics England) with the REal-time Assessment of Community Transmission (REACT) programme that is responsible for understanding how the virus spreads in the community. GenOMICC and Genomics England are already comparing the genomes and health data from two groups of people who tested positive for COVID-19; people recruited through hospitals who had severe COVID-19 against people who tested positive for COVID-19 but who either had no, or only mild, symptoms. The two groups are being matched for age and ethnicity. By partnering the REACT programme with this ongoing genome comparison we will be able to explore the interaction of the genome with the environment in up to 8,000 individuals who had mild or no symptoms and increase our knowledge about why these people responded more mildly than others. We will be using a so-called "multi-omics" approach, which means that we will not only be looking at the genome's instructions but how they are interpreted by the body at many different levels. This information is critical to understanding who is most at risk in the future and in being able to predict, prevent or treat COVID-19 more effectively. This partnership gives the best possible chance of recruiting the right number of people who have been infected with the virus but experienced no or only mild symptoms, undertaking the necessary research and of getting vital answers quickly in order to provide an effective response to the ongoing COVID-19 pandemic.

COVID-19 is a new infectious disease responsible for a global pandemic and presenting major knowledge gaps with respect to disease susceptibility, severity of infection and disease mechanisms. While most individuals infected with SARS-CoV-2 virus are asymptomatic or mildly affected, a minority require hospitalisation, need assisted ventilation and some progress to respiratory or other organ failure/death. The mechanisms for these differences in susceptibility and severity of disease are unknown, but are likely to encompass a combination of genetic susceptibility and gene-environment interactions that lead to downstream biochemical disturbances. We have assembled a multi-disciplinary international team of leading researchers to address these knowledge gaps by applying a multi-omics approach encompassing whole genome sequencing (WGS), proteomic, transcriptomic and metabolomic analyses to mild/asymptomatic cases. We will delineate biological pathways that are protective of or deleterious to the response to SARS-CoV-2 infection that may identify novel targets for treatment and ultimately prevention of the disease (e.g. vaccine response). The partnership between REal-time Assessment of Community Transmission (REACT) and Genomics England (REACT-GE) brings together the DHSC-funded GenOMICC programme and the community-wide viral antigen and seroprevalence surveillance (REACT) platform identifying mild/asymptomatic SARS-CoV-2 positive people in the population. We propose that c.8000 mild/asymptomatic participants are recruited through the REACT study for which we will obtain a multi-omic resource to sit alongside WGS already funded, and thus enhance the biological richness and utility of the resource for drug target discovery. Specifically we propose to undertake a series of proteomics, transcriptomics and metabolomics analyses alongside WGS to provide an unparalleled resource for multiomic phenotyping and discovery.