Host Genetics in COVID-19
As the SARS-CoV-2 virus continued to spread globally, it became clear that the symptoms and severity of infection experienced by patients varied across a broad spectrum, from being asymptomatic carriers to experiencing severe symptoms in 1 or more organ systems in the body, resulting in death. This variability suggested that host genetics and other host factors may play a role in determining the severity of COVID-19 infection. The MVP dataset, with genetic and health information on > 600,000 MVP participants, provided an ideal dataset to explore host contributions to COVID-19.
In late spring 2020, the MVP executive committee issued a call to the MVP research community to propose study aims around the COVID-19 pandemic that could leverage the phenotypic and genetic data and resources. The MVP quickly formed 6 rapid-response scientific working groups. Their mission was to cultivate collaboration and inclusivity and to coordinate COVID-19 research questions. A steering committee composed of the MVP executive committee, staff from computational environments, working group cochairs, and an administrator, who was responsible for daily oversight of the working groups. In addition, the ORD COVID-19 steering committee reviewed and approved research activities to ensure scientific rigor, as well as alignment with overall ongoing research activities.
The MVP COVID-19 working groups included dozens of researchers who used MVP data to identify disease mechanisms; understand the impact of host genetics on susceptibility, morbidity, and mortality; and identify potential targets for treatments and therapies. The working groups were further supported by MVP analysts to work cross-functionally on genomics, phenomics, statistical genetics, and PheWAS. Each working group chair was responsible for prioritizing concepts and moving them forward in coordination with the MVP and ORD COVID-19 steering committees. An overview of the MVP COVID-19 working groups follows (Table).4-9
Druggable genome. This working group researched drug-repurposing opportunities to prevent severe COVID-19, defined as hospitalization with oxygen therapy (high flow), intubation, mechanical ventilation, vasopressors, dialysis, or death from COVID-19; and prevent complications in patients hospitalized by COVID-19.
Pharmacogenomics. This working group focused on 2 main aims: the impact of apolipoprotein L1 risk variants on acute kidney injury (AKI) and death in Black veterans with COVID-19; and pharmacogenetic analysis of remdesivir-induced liver chemistry abnormalities.
Disease mechanisms. Understanding the underlying pathways and mechanisms behind COVID-19 has been a difficult but important challenge overall in the scientific community. This working group investigated specific genetic markers and effects on COVID-19, including polygenic predisposition to venous thromboembolism associated with increased COVID-19 susceptibility; renal comorbidities and new AKI and unfavorable outcomes among COVID-19–positive sickle cell trait carriers; and mucin 5B, oligomeric mucus/gel-forming gene polymorphism, and protective effects in COVID-19 infection.
Genomics for risk prediction, polygenic risk scores, and mendelian randomization. Risk prediction for COVID-19 has been widely studied mostly aiming at comorbidities and preexisting conditions. The MVP cohort provided a unique opportunity to understand how genetic information can enhance our understanding of COVID-19 risk. This working group focused on: (1) ABO blood group typing and the protective effects of the O blood group on COVID-19 infection; (2) polygenic risk scores and COVID-19 outcomes; (3) human leukocyte antigen typing and COVID-19 outcomes; and (4) a transcriptome-wide association study of COVID-19–positive MVP participants.
Genome-Wide Association Study (GWAS) and Downstream Analysis. This working group performed GWAS of the main COVID-19 outcomes. Results from GWAS unveiled new genetic loci to suggest further investigation on these candidate genes. The results were used by other MVP COVID-19 working groups for their activities. The results also contributed to external collaborations, such as the COVID-19 Host Genetics Initiative.
COVID-19–Related PheWAS. This working group focused on understanding the potential clinical significance of genetic variants associated with susceptibility to, or outcomes of, COVID-19 infection. They worked to identify traits that share genetic variants associated with severe COVID-19 from the Host Genetics Initiative. The group also studied the phenotypic consequences of acquired mosaic chromosomal alterations with early data linking to COVID-19 susceptibility.