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

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 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

A first update on mapping the human genetic architecture of COVID-19

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The Gondwana connections of northern Patagonia

A multidisciplinary study (U–Pb sensitive high-resolution ion microprobe geochronology, Hf and O isotopes in zircon, Sr and Nd isotopes in whole-rocks, as well as major and trace element geochemistry) has been carried out on granitoid samples from the area west of Valcheta, North Patagonian Massif, Argentina. These confirm the Cambrian age of the Tardugno Granodiorite (528 ± 4 Ma) and the Late Permian age of granites in the central part of the Yaminué complex (250 Ma). Together with petrological and structural information for the area, we consider a previously suggested idea that the Cambrian and Ordovician granites of northeastern Patagonia represent continuation of the Pampean and Famatinian orogenic belts of the Sierras Pampeanas, respectively. Our interpretation does not support the hypothesis that Patagonia was accreted in Late Palaeozoic times as a far-travelled terrane, originating in the Central Transantarctic Mountains, and the arguments for and against this idea are reviewed. A parautochthonous origin is preferred with no major ocean closure between the North Patagonian Massif and the Sierra de la Ventana fold belt. Supplementary material: U–Pb SHRIMP analytical data, geochemical analyses and sample global positioning system locations are available at www.geolsoc.org.uk/SUP18722

The Gondwana connections of northern Patagonia

<p>A multidisciplinary study (U–Pb sensitive high-resolution ion microprobe geochronology, Hf and O isotopes in zircon, Sr and Nd isotopes in whole-rocks, as well as major and trace element geochemistry) has been carried out on granitoid samples from the area west of Valcheta, North Patagonian Massif, Argentina. These confirm the Cambrian age of the Tardugno Granodiorite (528 ± 4 Ma) and the Late Permian age of granites in the central part of the Yaminué complex (250 Ma). Together with petrological and structural information for the area, we consider a previously suggested idea that the Cambrian and Ordovician granites of northeastern Patagonia represent continuation of the Pampean and Famatinian orogenic belts of the Sierras Pampeanas, respectively. Our interpretation does not support the hypothesis that Patagonia was accreted in Late Palaeozoic times as a far-travelled terrane, originating in the Central Transantarctic Mountains, and the arguments for and against this idea are reviewed. A parautochthonous origin is preferred with no major ocean closure between the North Patagonian Massif and the Sierra de la Ventana fold belt. </p

Hf and Nd isotopes in Early Ordovician to Early Carboniferous granites as monitors of crustal growth in the Proto-Andean margin of Gondwana

We report the first study integrating in situ U–Pb and Hf isotope data from magmatic zircon and whole-rock Sm–Nd isotope data for granitic rocks of the Sierras Pampeanas, Argentina, in order to evaluate the Palaeozoic growth of the proto-Andean margin of Gondwana. Early–Middle Ordovician granitic magmatism is by far the most voluminous of the Sierras Pampeanas and represents the most significant magmatic event. These calc-alkaline granitoids were intruded at an active continental margin. εHft values range from − 3.3 to − 14.7 and εNdt from − 3.3 to − 6.3 (t = 473 Ma), with average TDM Hf and TDM Nd ranging from 1.5 to 2.2 Ga and 1.4 to 1.7 Ga, respectively. Middle–Late Devonian magmatism occurred in the foreland, away from the orogenic front in the west, and included F-U-REE rich A-type granites. The Achala granite, the largest batholith in the Sierras Pampeanas, has εHft and εNdt values ranging from − 3.6 to − 5.8 and − 4.0 to − 6.5, respectively (t = 369 Ma). Small scattered Early Carboniferous A-type granite plutons were intruded in a dominantly extensional setting and have εHft and εNdt values ranging from − 6.7 to + 2.2 and − 0.5 to − 3.6, respectively (t = 341 Ma). The generation of Ordovician and Devonian magmas dominantly involved crustal reworking and stabilization rather than the formation of new continental crust by juvenile material accretion, whereas Carboniferous magmatism resulted in part from reworking of supracrustal material, but with variable addition of juvenile magmas