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GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.

ABSTRACT: 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).

SUBMITTER: Pairo-Castineira E

PROVIDER: S-EPMC10208981 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.

Pairo-Castineira Erola E Rawlik Konrad K Bretherick Andrew D AD Qi Ting T Wu Yang Y Nassiri Isar I McConkey Glenn A GA Zechner Marie M Klaric Lucija L Griffiths Fiona F Oosthuyzen Wilna W Kousathanas Athanasios A Richmond Anne A Millar Jonathan J Russell Clark D CD Malinauskas Tomas T Thwaites Ryan R Morrice Kirstie K Keating Sean S Maslove David D Nichol Alistair A Semple Malcolm G MG Knight Julian J Shankar-Hari Manu M Summers Charlotte C Hinds Charles C Horby Peter P Ling Lowell L McAuley Danny D Montgomery Hugh H Openshaw Peter J M PJM Begg Colin C Walsh Timothy T Tenesa Albert A Flores Carlos C Riancho José A JA Rojas-Martinez Augusto A Lapunzina Pablo P Yang Jian J Ponting Chris P CP Wilson James F JF Vitart Veronique V Abedalthagafi Malak M Luchessi Andre D AD Parra Esteban J EJ Cruz Raquel R Carracedo Angel A Fawkes Angie A Murphy Lee L Rowan Kathy K Pereira Alexandre C AC Law Andy A Fairfax Benjamin B Hendry Sara Clohisey SC Baillie J Kenneth JK

Nature 20230517 7962

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 illnes ...[more]

PMID: 37198478

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Project description:BackgroundOvine footrot caused by Dichelobacter nodosus (D. nodosus) is a contagious disease with serious economic and welfare impacts in sheep production systems worldwide. A better understanding of the host genetic architecture regarding footrot resistance/susceptibility is crucial to develop disease control strategies that efficiently reduce infection and its severity. A genome-wide association study was performed using a customized SNP array (47,779 SNPs in total) to identify genetic variants associated to footrot resistance/susceptibility in two Portuguese native breeds, i.e. Merino Branco and Merino Preto, and a population of crossbred animals. A cohort of 1375 sheep sampled across 17 flocks, located in the Alentejo region (southern Portugal), was included in the analyses.ResultsPhenotypes were scored from 0 (healthy) to 5 (severe footrot) based on visual inspection of feet lesions, following the Modified Egerton System. Using a linear mixed model approach, three SNPs located on chromosome 24 reached genome-wide significance after a Bonferroni correction (p < 0.05). Additionally, six genome-wide suggestive SNPs were identified each on chromosomes 2, 4, 7, 8, 9 and 15. The annotation and KEGG pathway analyses showed that these SNPs are located within regions of candidate genes such as the nonsense mediated mRNA decay associated PI3K related kinase (SMG1) (chromosome 24) and the RALY RNA binding protein like (RALYL) (chromosome 9), both involved in immunity, and the heparan sulfate proteoglycan 2 (HSPG2) (chromosome 2) and the Thrombospodin 1 (THBS1) (chromosome 7) implicated in tissue repair and wound healing processes.ConclusionThis is the first attempt to identify molecular markers associated with footrot in Portuguese Merino sheep. These findings provide relevant information on a likely genetic association underlying footrot resistance/susceptibility and the potential candidate genes affecting this trait. Genetic selection strategies assisted on the information obtained from this study could enhance Merino sheep-breeding programs, in combination with farm management strategies, for a more effective and sustainable long-term solution for footrot control.

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GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.

Publications

GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.

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