Mapping the human genetic architecture of COVID-19

Matters Arising to this article was published on 03 August 2022, available online at: https://doi.org/10.1038/s41586-022-04826-7 . A second Matters Arising to this article was published on 06 September 2023, available online at: https://doi.org/10.1038/s41586-023-06355-3 .Data availability: Summary statistics generated by the COVID-19 HGI are available at https://www.covid19hg.org/results/r5/ and are available in the GWAS Catalog (study code GCST011074). The analyses described here include the freeze-5 data. COVID-19 HGI continues to regularly release new data freezes. Summary statistics for non-European ancestry samples are not currently available due to the small individual sample sizes of these groups, but results for lead variants of 13 loci are reported in Supplementary Table 3. Individual level data can be requested directly from contributing studies, listed in Supplementary Table 1. We used publicly available data from GTEx (https://gtexportal.org/home/), the Neale lab (https://www.nealelab.is/uk-biobank/), Finucane lab (https://www.finucanelab.org), the FinnGen Freeze 4 cohort (https://www.finngen.fi/en/access_results) and the eQTL catalogue release 3 (https://www.ebi.ac.uk/eqtl/).Code availability: The code for summary statistics lift-over, the projection PCA pipeline including precomputed loadings and meta-analyses are available on GitHub (https://github.com/covid19-hg/) and the code for the Mendelian randomization and genetic correlation pipeline is available on GitHub at https://github.com/marcoralab/MRcovid.Reporting summary: Further information on research design is available in the Nature Research Reporting Summary linked to this paper online at: https://www.nature.com/articles/s41586-021-03767-x#MOESM2 .Supplementary information is available onlne at: https://www.nature.com/articles/s41586-021-03767-x#Sec24 .Extended data figures and tables are available online at: https://www.nature.com/articles/s41586-021-03767-x#Sec23 .Copyright © The Author(s) 2021. The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. 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. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. 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 report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. 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. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. 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. 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. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. 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 across19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases(3-7). They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. 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. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.Radiolog

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The structure of business preferences and Eurozone crisis policies

What explains business views regarding policy preferences in the Eurozone crisis? Although recent literature examines the impact of the crisis on citizen views, few studies examine business preferences towards adjustment policies. We present unique data from a new representative survey of 500 high-level firm representatives from Spain to test theories about such preferences, in particular views about the euro, fiscal austerity, and wage devaluation, as well as plausible mechanisms for such preferences. We test three broad families of theories to explain such preferences, focusing on the role of structural firm characteristics, economic hardship, and political leanings of firm managers. We find that first, there is a strong conservative position regarding all of these policies. Second, we find that contra conventional approaches to explaining preferences, for the domestic policies (but not for euro views), the political leanings of firms matter much more than baseline structural characteristics. Third, we find that surprisingly economic hardship does not cause firms to demand more left-wing policies, as it might for voters; in fact, firms that have suffered are likely to be more skeptical of such measures. These findings indicate the need to better measure political orientations of firm respondents and suggest that this is a larger division among firms than previously recognized

Selling austerity: Preferences for fiscal adjustment during the Eurozone crisis

What explains individual preferences for austerity during the eurozone crisis? To what extent are such preferences affected by the specific content of austerity policies or EU-related factors? To address these questions, we present new data and embedded experiments that test theories of austerity preferences, from a survey of a crisis-hit country, Spain. We find little support for austerity as conventionally measured, but such support can increase if specific reasons or benefits are made salient. The endorsement by the EU has no effect on austerity support, but support for spending wanes when tax increases and concerns about fiscal commitments to the EU are made salient. The results help understand how unpopular policies such as austerity might be sometimes palatable to large segments of the general public

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The structure of business preferences and Eurozone crisis policies

What explains business views regarding policy preferences in the Eurozone crisis? Although recent literature examines the impact of the crisis on citizen views, few studies examine business preferences towards adjustment policies. We present unique data from a new representative survey of 500 high-level firm representatives from Spain to test theories about such preferences, in particular views about the euro, fiscal austerity, and wage devaluation, as well as plausible mechanisms for such preferences. We test three broad families of theories to explain such preferences, focusing on the role of structural firm characteristics, economic hardship, and political leanings of firm managers. We find that first, there is a strong conservative position regarding all of these policies. Second, we find that contra conventional approaches to explaining preferences, for the domestic policies (but not for euro views), the political leanings of firms matter much more than baseline structural characteristics. Third, we find that surprisingly economic hardship does not cause firms to demand more left-wing policies, as it might for voters; in fact, firms that have suffered are likely to be more skeptical of such measures. These findings indicate the need to better measure political orientations of firm respondents and suggest that this is a larger division among firms than previously recognized

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