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Whole-genome sequencing reveals host factors underlying critical COVID-19.

ABSTRACT: Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care¹ or hospitalization^2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

SUBMITTER: Kousathanas A

PROVIDER: S-EPMC9259496 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Whole-genome sequencing reveals host factors underlying critical COVID-19.

Kousathanas Athanasios A Pairo-Castineira Erola E Rawlik Konrad K Stuckey Alex A Odhams Christopher A CA Walker Susan S Russell Clark D CD Malinauskas Tomas T Wu Yang Y Millar Jonathan J Shen Xia X Elliott Katherine S KS Griffiths Fiona F Oosthuyzen Wilna W Morrice Kirstie K Keating Sean S Wang Bo B Rhodes Daniel D Klaric Lucija L Zechner Marie M Parkinson Nick N Siddiq Afshan A Goddard Peter P Donovan Sally S Maslove David D Nichol Alistair A Semple Malcolm G MG Zainy Tala T Maleady-Crowe Fiona F Todd Linda L Salehi Shahla S Knight Julian J Elgar Greg G Chan Georgia G Arumugam Prabhu P Patch Christine C Rendon Augusto A Bentley David D Kingsley Clare C Kosmicki Jack A JA Horowitz Julie E JE Baras Aris A Abecasis Goncalo R GR Ferreira Manuel A R MAR Justice Anne A Mirshahi Tooraj T Oetjens Matthew M Rader Daniel J DJ Ritchie Marylyn D MD Verma Anurag A Fowler Tom A TA 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 Elliott Paul P Walsh Timothy T Tenesa Albert A Fawkes Angie A Murphy Lee L Rowan Kathy K Ponting Chris P CP Vitart Veronique V Wilson James F JF Yang Jian J Bretherick Andrew D AD Scott Richard H RH Hendry Sara Clohisey SC Moutsianas Loukas L Law Andy A Caulfield Mark J MJ Baillie J Kenneth JK

Nature 20220307 7917

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care<sup>1</sup> or hospitalization<sup>2-4</sup> after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically i ...[more]

PMID: 35255492

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Project description:HIV infection continues to be a major global public health issue. The population heterogeneity in susceptibility or resistance to HIV-1 and progression upon infection is attributable to, among other factors, host genetic variation. Therefore, identifying population-specific variation and genetic modifiers of HIV infectivity can catapult the invention of effective strategies against HIV-1 in African populations. Here, we investigated whole genome sequences of 390 unrelated HIV-positive and -negative individuals from Botswana. We report 27.7 million single nucleotide variations (SNVs) in the complete genomes of Botswana nationals, of which 2.8 million were missing in public databases. Our population structure analysis revealed a largely homogenous structure in the Botswana population. Admixture analysis showed elevated components shared between the Botswana population and the Niger-Congo (65.9%), Khoe-San (32.9%), and Europeans (1.1%) ancestries in the population of Botswana. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated. The most deleterious variants were enriched in five genes: ACTRT2 (the Actin Related Protein T2), HOXD12 (homeobox D12), ABCB5 (ATP binding cassette subfamily B member 5), ATP8B4 (ATPase phospholipid transporting 8B4) and ABCC12 (ATP Binding Cassette Subfamily C Member 12). These genes are enriched in the glycolysis and gluconeogenesis (p < 2.84e-6) pathways and therefore, may contribute to the emerging field of immunometabolism in which therapy against HIV-1 infection is being evaluated. Published transcriptomic evidence supports the role of the glycolysis/gluconeogenesis pathways in the regulation of susceptibility to HIV, and that cumulative effects of genetic modifiers in glycolysis/gluconeogenesis pathways may potentially have effects on the expression and clinical variability of HIV-1. Identified genes and pathways provide novel avenues for other interventions, with the potential for informing the design of new therapeutics.

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Whole-genome sequencing reveals host factors underlying critical COVID-19.

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Whole-genome sequencing reveals host factors underlying critical COVID-19.

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