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The average age of the participants with COVID-19 across studies was 55 years (Supplementary Table 1). Controls for all three analyses were selected as genetically ancestry-matched samples without known SARS-CoV-2 infection, if that information was available (Methods). These included (1) critically ill cases of COVID-19 defined as those individuals who required respiratory support in hospital or who died due to the disease (2) cases of moderate or severe COVID-19 defined as those participants who were hospitalized due to symptoms associated with the infection and (3) all cases with reported SARS-CoV-2 infection regardless of symptoms (Methods). We performed case–control meta-analyses in three main categories of COVID-19 disease according to predefined and partially overlapping phenotypic criteria. An overview of the study design is provided in Extended Data Fig. The data included studies from populations of different genetic ancestries, including European, admixed American, African, Middle Eastern, South Asian and East Asian individuals (Supplementary Table 1). Overall, the COVID-19 HGI combined genetic data from 49,562 cases and 2 million controls across 46 distinct studies (Fig. Here, we report the latest results of meta-analyses of 46 studies from 19 countries (Fig. The COVID-19 Host Genetics Initiative (COVID-19 HGI) ( ) 17 is an international, open-science collaboration to share scientific methods and resources with research groups across the world with the goal to robustly map the host genetic determinants of SARS-CoV-2 infection and the severity of the resulting COVID-19 disease. However, much remains unknown about the genetic basis of susceptibility to SARS-CoV-2 and severity of COVID-19. At the same time, several genome-wide association studies that investigate the contribution of common genetic variation 12, 13, 14, 15 to COVID-19 have provided robust support for the involvement of several genomic loci associated with COVID-19 severity and susceptibility, with the strongest and most robust finding for severity being at the 3p21.31 locus 12, 13, 14, 15, 16. Further supporting this line of inquiry, rare loss-of-function variants in genes involved in the type I interferon response may be involved in severe forms of COVID-19 9, 10, 11. Genetic factors contributing to COVID-19 susceptibility and severity may provide new biological insights into disease pathogenesis and identify mechanistic targets for therapeutic development or drug repurposing, as treating the disease remains a highly important goal despite the recent development of vaccines. Although established host factors correlate with disease severity (for example, increasing age, being a man and higher body-mass index 1), these risk factors alone do not explain all of the variability in disease severity observed across individuals. One of the most remarkable features of SARS-CoV-2 infection is the variation in consequences, which range from asymptomatic to life-threatening, viral pneumonia and acute respiratory distress syndrome 8. The COVID-19 pandemic, caused by infection with SARS-CoV-2, has resulted in an enormous health and economic burden worldwide. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. They also represent potentially actionable mechanisms in response to infection. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3, 4, 5, 6, 7. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1, 2, host genetics may also be important. The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Magazines, word of mouth and rap tabloids were saying I didn't have it any more. He stated: For the last couple of years, there's been a lot of talk out on the streets about whether or not I can still hold my own, whether or not I'm still good at producing. These doubts came from the fact that he had not released a solo studio album since (1992). Dre spoke about his motivation to record the album and how he felt that he had to prove himself to fans and media again after doubts arose over his production and rapping ability. Background In an interview with The New York Times, Dr.
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