Overall, the COVID-19 HGI combined genetic data from 49,562 cases and 2 million controls across 46 distinct studies (Fig. 1). 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). An overview of the study design is provided in Extended Data Fig. 1. We performed case-control meta-analyses in three main categories of COVID-19 disease according to predefined and partially overlapping phenotypic criteria. 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). Controls for all three analyses were selected as genetically ancestry-matched samples without known SARS-CoV-2 infection, if that information was available (Methods). The average age of the participants with COVID-19 across studies was 55 years (Supplementary Table 1). We report quantile-quantile plots in Supplementary Fig. 1 and ancestry principal component plots for contributing studies in Extended Data Fig. 2.
Across our three analyses, we reported a total of 13 independent genome-wide significant loci associated with COVID-19 (the threshold of P < 1.67 × 10−8 is adjusted for multiple trait testing) (Supplementary Table 2), most of which were shared between two or more COVID-19 phenotypes. Two of these loci are in very close proximity within the 3p21.31 region, which was previously reported as a single locus associated with COVID-19 severity12,13,14,15,16 (Extended Data Fig. 3). Overall, we find six genome-wide significant associations for critical illness due to COVID-19, using data from 6,179 cases and 1,483,780 controls from 16 studies (Extended Data Fig. 4). Nine genome-wide significant loci were detected for moderate to severe hospitalized COVID-19 (including five of the six critical illness loci) from an analysis of 13,641 cases of COVID-19 and 2,070,709 controls across 29 studies (Fig. 2a, top). Finally, seven loci reached genome-wide significance in the analysis using data for all available 49,562 reported cases of SARS-CoV-2 infection and 1,770,206 controls, using data from a total of 44 studies (Fig. 2a, bottom). The proportion of cases with non-European genetic ancestry for each of the three analyses was 23%, 29% and 22%. We report the results for the lead variants at the 13 loci in different ancestry-group meta-analyses in Supplementary Table 3. We note that two loci, tagged by lead variants rs1886814 and rs72711165, had higher allele frequencies in southeast Asian (rs1886814; 15%) and East Asian genetic ancestry (rs72711165; 8%) whereas the minor allele frequencies in European populations were less than 3%. This highlights the value of including data from diverse populations for genetic discovery. We discuss the replication of previous findings and the new discoveries from these three analyses in the Supplementary Note.
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