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).

NCT01003639, Post-results.

No abstract

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.

Introduction Although rare, nonthrombotic causes of venous obstruction do occur. Their ultrasound findings can mimic deep vein thrombosis (DVT). We sought to examine the ultrasound appearance of these tumors to determine whether their differentiation from DVT was possible. Case Report Two patients, in whom a DVT was initially suspected, were subsequently diagnosed with intravascular tumors: a leiomyosarcoma and a hemangioma. The first patient presented with thigh pain, and an initial diagnosis of long saphenous vein (LSV) and common femoral vein thrombosis was made. The apparent thrombus remained unchanged despite anticoagulation. Proliferation of the lesion outside of the LSV developed, resulting in a review of the diagnosis, and surgical resection was performed. A histological diagnosis of leiomyosarcoma was made. The second patient presented with leg swelling and an initial diagnosis of External Iliac vein thrombosis was made. Further ultrasound assessments demonstrated arterialized flow within the lesion and surgical resection was performed, with a histological diagnosis of intravascular epithelioid hemangioma. Results The B-mode appearance was similar for both. The presence of arterialized flow within the lesions is helpful but may not be diagnostic because of recent reports that neovascularization may develop within thrombus. Conclusion Suspicion needs to be raised in a patient presenting with an unprovoked DVT or when conventional treatment does not result in improvement of symptoms; as well as when prolonged arterialization is identified within the thrombus. These signs can alert the clinician to a possible non-thrombotic mechanism of venous obstruction.