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

Fig. 14. A, Callograptus bridgecreekensis n in Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales

Fig. 14. A, Callograptus bridgecreekensis n.sp., AM F114569a, holotype, F14; B,C, Callograptus rigbyi n.sp., respectively AM F114651a, holotype, BF28, and paratype AM F114643, W885. Scale bars 1 mm. Note that in Fig. 14B the isolated autothecae of Cyclograptus? australis can be seen at bottom right and on Fig. 14C a specimen of Acanthograptus praedeckeri occurs at the top.Published as part of <i>Rickards, R.B., Chapman, A.J., Wright, A.J. & Packham, G.H, 2003, Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales, pp. 305-330 in Records of the Australian Museum 55 (3)</i> on page 320, DOI: 10.3853/j.0067-1975.55.2003.1387, <a href="http://zenodo.org/record/10092612">http://zenodo.org/record/10092612</a&gt

Fig. 9. A–E in Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales

Fig. 9. A–E, illustrating contrasting stipe and dissepimental patterns in distal parts of colonies: A, Dictyonema cf. delicatulum, AM F114749; B, Dictyonema williamsae n.sp., AM F114565, holotype; C, Dictyonema falciferum, AM F114750; D, Dictyonema venustum, AM F114648a, F14; E, Dictyonema paululum australis n.subsp., holotype AM F114757. Scale bars 1 mm.Published as part of <i>Rickards, R.B., Chapman, A.J., Wright, A.J. & Packham, G.H, 2003, Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales, pp. 305-330 in Records of the Australian Museum 55 (3)</i> on page 316, DOI: 10.3853/j.0067-1975.55.2003.1387, <a href="http://zenodo.org/record/10092612">http://zenodo.org/record/10092612</a&gt

Fig. 16. A, Callograptus ulahensis n in Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales

Fig. 16. A, Callograptus ulahensis n.sp., AM F114760, holotype, BF15; B, Callograptus niagarensis, AM F114739, W885; C–E, Pseudodictyonema graptolithorum, respectively AM F114755, AM F114753 and AM F114645, all from F14. Scale bars 1 mm.Published as part of <i>Rickards, R.B., Chapman, A.J., Wright, A.J. & Packham, G.H, 2003, Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales, pp. 305-330 in Records of the Australian Museum 55 (3)</i> on page 322, DOI: 10.3853/j.0067-1975.55.2003.1387, <a href="http://zenodo.org/record/10092612">http://zenodo.org/record/10092612</a&gt

Fig. 2 in Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales

Fig. 2. Dendroid graptolite localities on the Bridge Creek sections.Published as part of <i>Rickards, R.B., Chapman, A.J., Wright, A.J. & Packham, G.H, 2003, Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales, pp. 305-330 in Records of the Australian Museum 55 (3)</i> on page 307, DOI: 10.3853/j.0067-1975.55.2003.1387, <a href="http://zenodo.org/record/10092612">http://zenodo.org/record/10092612</a&gt

Fig. 6. A,B, Dendrograptus avonleaensis n in Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales

Fig. 6. A,B, Dendrograptus avonleaensis n.sp., respectively AM F114650 and holotype AM F114646a, both from BF14; C, Dictyonema cf. delicatulum, AM F114749, F14. Scale bars 1 mm.Published as part of <i>Rickards, R.B., Chapman, A.J., Wright, A.J. & Packham, G.H, 2003, Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales, pp. 305-330 in Records of the Australian Museum 55 (3)</i> on page 313, DOI: 10.3853/j.0067-1975.55.2003.1387, <a href="http://zenodo.org/record/10092612">http://zenodo.org/record/10092612</a&gt

Fig. 4. A–G in Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales

Fig. 4. A–G, different types of bithecae: A, Bulman's (1928, 1933) Type 1 with bitheca n+1 opening along the lateral wall of autotheca n. This is the most common of autothecal/bithecal relationships; B,C, Bulman's (1928, 1933) Type 2 in which the bithecal aperture opens inside the autothecal tube or aperture; D, Bulman's (1928, 1933) Type 3 where the n+1 bithecal aperture is located on the dorsal side of the aperture of autotheca n; E, Bulman's (1928, 1933) Type 4 in which the bithecal tube n+1 passes between the dorsal wall of autotheca n and the ventral wall of autotheca n+ 1; F,G, Bulman's (1928, 1933) Type 5 a modification of Type 4 in which the bithecal tube turns proximally or distally before the bithecal aperture is reached; H–M, autothecal variation in Dictyonema species; H, autothecal aperture is the termination of a simple tube; I, the ventral lip projects as a short, sharp denticle; J, the ventral lip projects as a spine which may or may not bifurcate; K, the ventral process is adorned with a large shield-like plate; L, the dorsal apertural process has plate-like process hanging more or less in front of the aperture; M, the apertural region is isolated from the ventral wall of the next autotheca; for the sake of simplicity in H–M the Type 1 bithecal arrangement is shown; fuselli omitted; a, autothecal aperture; b, bithecal aperture; these structures are described or commented upon in various places in the text.Published as part of <i>Rickards, R.B., Chapman, A.J., Wright, A.J. & Packham, G.H, 2003, Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales, pp. 305-330 in Records of the Australian Museum 55 (3)</i> on page 311, DOI: 10.3853/j.0067-1975.55.2003.1387, <a href="http://zenodo.org/record/10092612">http://zenodo.org/record/10092612</a&gt

Fig. 13. A–D, Dictyonema muirae n in Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales

Fig. 13. A–D, Dictyonema muirae n.sp., respectivelyAM F114763, BF14, AM F114775, F14, holotype AM F114762, F14, and AM F114764, BF14 proximal part of colony attached to pebble of phosphate; E–G, Dictyonema warrisi n.sp., respectively AM F114647, F14, holotype AM F114717, W885 and AM F114647, F14, with stipes more proximal than E; H, Dictyonema sp. 1, AM F11475, F14. Scale bars 1 mm; shading on C indicates badly preserved area.Published as part of <i>Rickards, R.B., Chapman, A.J., Wright, A.J. & Packham, G.H, 2003, Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales, pp. 305-330 in Records of the Australian Museum 55 (3)</i> on page 318, DOI: 10.3853/j.0067-1975.55.2003.1387, <a href="http://zenodo.org/record/10092612">http://zenodo.org/record/10092612</a&gt

Fig. 22. A,B. Thallograptus christoffersonae n in Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales

Fig. 22. A,B. Thallograptus christoffersonae n.sp.: A, AM F114765, stipe development from basal holdfast, BF14 and B, AM F114746, holotype, F14; C, Koremagraptus obscurus n.sp. AM F114745,Published as part of <i>Rickards, R.B., Chapman, A.J., Wright, A.J. & Packham, G.H, 2003, Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales, pp. 305-330 in Records of the Australian Museum 55 (3)</i> on page 327, DOI: 10.3853/j.0067-1975.55.2003.1387, <a href="http://zenodo.org/record/10092612">http://zenodo.org/record/10092612</a&gt

Fig. 19. A,B, Stelechocladia praeattenuata n in Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales

Fig. 19. A,B, Stelechocladia praeattenuata n.sp.: A, AM F114743, holotype, and B, AM F114744, both BF18; C, Acanthograptus praedeckeri praedeckeri n.sp., AM F114629a, F14. Scale bars 1 mm.Published as part of <i>Rickards, R.B., Chapman, A.J., Wright, A.J. & Packham, G.H, 2003, Dendroid and Tuboid Graptolites from the Llandovery (Silurian) of the Four Mile Creek Area, New South Wales, pp. 305-330 in Records of the Australian Museum 55 (3)</i> on page 325, DOI: 10.3853/j.0067-1975.55.2003.1387, <a href="http://zenodo.org/record/10092612">http://zenodo.org/record/10092612</a&gt