Initially, GWAS-identified haplotypes were screened for potential protein-coding sequence variants. This combines computational and wet lab approaches to delineate the identity of causative variants, the cell types involved and effector genes. We developed a comprehensive platform for decoding the effects of sequence variation identified by GWAS 16 (Extended Data Fig. Deciphering the variants that affect enhancers is challenging because many enhancers are only active in specific cell types or at specific times enhancers are often distant in the linear DNA sequence (often 10 4–10 6 base pairs (bp)) from the genes they control and the effects of sequence changes are not straightforward to predict. Many are thought to lie within cis-regulatory elements 17, such as enhancers, which are short DNA sequences that often control tissue- and developmental stage-specific gene expression. The remaining variants and their target gene(s) can be very difficult to decode. Alteration of the protein-coding sequence or RNA splicing, both of which are relatively straightforward to disentangle, account for fewer than 20% of associations in polygenic disease 16. Third, there are multiple mechanisms by which variants can have an effect. Second, the genetic signals are completely cell type-agnostic, which makes it challenging to identify appropriate experimental models for further investigation. First, a causative variant is usually in linkage disequilibrium (LD) with many other variants and these can take different forms (SNPs, insertions, deletions and structural polymorphisms). Identifying the causal gene(s) and mechanism(s) behind GWAS hits poses several challenges. Additionally, the risk variants at this locus are carried by >60% of individuals with South Asian ancestry (SAS), compared to 15% of European ancestry (EUR) groups, partially explaining the ongoing higher death rate in this population in the UK 14, 15. 9, 10) and an over twofold increased risk of mortality for individuals under 60 (ref. The 3p21.31 risk haplotype, which arises from Neanderthal DNA 12 and is currently unexplained with regards to the causal variant(s), causal gene(s) and specific role in COVID-19, confers a twofold increased risk of respiratory failure from COVID-19 (refs. Both studies identified a region of chromosome 3p21.31 as having the strongest association, while a third study also identified this locus as conferring susceptibility to infection 11. Two large GWAS were carried out to determine whether common variants drive susceptibility to severe COVID-19 (refs. Genome-wide association studies (GWAS) are important for identifying candidate genes and pathways that predispose to complex diseases 7 genetically validated drug targets are more likely to lead to approved drugs 8. However, COVID-19 can cause multiple organ failure through cytokine release, microvascular and macrovascular thrombosis, endothelial damage, acute kidney injury and myocarditis 4, 5, 6. The predominant cause of mortality is pneumonia and severe acute respiratory distress syndrome 3. The COVID-19 pandemic is estimated to have caused over 4.6 million deaths so far 1, 2. Since the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may represent a therapeutic target. We conclude that pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely responsible for the 3p21.31-associated risk. Selective spatial transcriptomic analysis of lung biopsies from patients with COVID-19 shows the presence of signals associated with epithelial–mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1. We show with chromosome conformation capture and gene-expression analysis that the rs17713054-affected enhancer upregulates the interacting gene, leucine zipper transcription factor like 1 ( LZTFL1). Here, using a combined multiomics and machine learning approach, we identify the gain-of-function risk A allele of an SNP, rs17713054G>A, as a probable causative variant. Genome-wide association studies identified the 3p21.31 region as conferring a twofold increased risk of respiratory failure. The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Nature Genetics volume 53, pages 1606–1615 ( 2021) Cite this article COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium,.Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus
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