Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Objective We aimed to assess the relationship between major air pollutants and the natural history and mortality of idiopathic pulmonary fibrosis (IPF). Methods We conducted a retrospective cohort study from 2013 to 2019 among 52 patients with IPF from the pneumology department of a tertiary hospital. According to their geocoded residential address, each patient was assigned a mean concentration of carbon monoxide (CO), nitrogen dioxide, particulate matter 2.5 and 10, ozone, and sulfur dioxide, as measured at a single surveillance station in central Madrid, Spain. We analyzed forced vital capacity (FVC), CO diffusing capacity, 6-minute walking test, degree of dyspnea, radiologic pattern, and signs of pulmonary hypertension in all patients. Results Patients’ mean age was 66 ± 10 years, and 79% were men. The mean predicted FVC was 78.9 ± 0.5%. Forty-two patients met the criteria for severe disease, and 18 patients died. Mortality was significantly associated with increased CO exposure (for each 0.1 mg/m2 increase: odds ratio 2.45, 95% confidence interval 1.39–4.56). We observed no association between any of the other investigated contaminants and IPF mortality or severity. Conclusions Air pollution, specifically that caused by carbon monoxide, can increase mortality in patients with IPF.

for their comments and suggestions. We also thank all participants at the internal seminar of the Banco de España for their comments. The views expressed in this paper are our own and do not necessarily reflect the views of the Banco de España or the European System of Central Banks (ESCB).

for their comments and suggestions. We also thank all participants at the internal seminar of the Banco de España for their comments. The views expressed in this paper are our own and do not necessarily reflect the views of the Banco de España or the European System of Central Banks (ESCB).

The Working Paper Series seeks to disseminate original research in economics and fi nance. All papers have been anonymously refereed. By publishing these papers, the Banco de España aims to contribute to economic analysis and, in particular, to knowledge of the Spanish economy and its international environment. The opinions and analyses in the Working Paper Series are the responsibility of the authors and, therefore, do not necessarily coincide with those of the Banco de España or the Eurosystem. The Banco de España disseminates its main reports and most of its publications via the Internet at the following website: http://www.bde.es. Reproduction for educational and non-commercial purposes is permitted provided that the source is acknowledged.

In the version of this article initially published, the name of Ana Margarita Baldión-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana María Baldion) and has now been amended in the HTML and PDF versions of the article.

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