SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

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 hospitalization2–4 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

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

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

peer reviewe

To close or not to close a patent foramen ovale: That is the question.

LEARNING OBJECTIVE #1: Recognizing that cardiac shunting often occur in setting of severe pulmonary hypertension (PH) and serves to relieve the severe increase in the right sided pressures. LEARNING OBJECTIVE #2: Recognizing one of the contraindications to patent foramen ovale (PFO) closure. CASE: A 65-year old female presented to Heart Failure clinic after a follow up transthoracic echocardiography (TTE). She complained of dyspnea, bilateral lower extremity edema, and right 4th digit pain. On physical exam, patient was noted to have darkening of her right 4th digits. She had hypoxia with higher oxygen requirement than baseline. Past medical history is significant for Interstitial Lung Disease (ILD), Pulmonary Hypertension (PH) groups (2 and 3), coronary artery disease with three prior stents, and chronic diastolic dysfunction. Her TTE showed EF of 50%, pulmonary artery systolic pressure of 60 mmHg, and large (greater than 20 bubbles) PFO, that is new, with predominantly right to left shunting across the atrial septum. Patient was hospitalized due to concern for paradoxical emboli and for her hypoxia. Right heart catheterization (RHC) was done that showedmean Pulmonary arterial pressure of 45 mmHg, wedge pressure of 8 mmHg, cardiac index of 2.13 L/min/m2, pulmonary vascular resistance of 840 dynes.sec.cm-5 (10.5 Wood units), and systemic vascular resistance (SVR) of 797.84 dynes.sec.cm-5 at rest. CT angiography was done that showed acute pulmonary embolus (PE) to segmental branches of right lower lobe and demonstrated stable ILD. An upper extremity arterial study demonstrated reduced perfusion to the right 4th digit attributable to a possible embolic event. High intensity heparin was initiated. Risks and Benefits of PFO closure were discussed at a multi-disciplinary meeting. Given that patient\u27s PVR \u3e 2/3 of SVR in the RHC, PFO closure was deferred. The patient was ultimately discharged on warfarin. IMPACT: Careful decision making in PFO closure should be pursued for PH patients, even in presence of a known indication for closure. One of the contraindications to PFO closure is the irreversible pulmonary hypertension (PVR \u3e2/3 SVR or pulmonary artery pressure \u3e 2/3 systemic arterial pressure). It is important to recognize that closure of PFO in those situations could precipitate decompensation of right ventricular (RV) function and sudden drop in cardiac output which could be fatal. DISCUSSION: While PFO closure may be pursued in cases of paradoxical emboli, a risk/benefit analysis, especially looking at PH, is necessary. In this case, acute PE is the likely cause of acute rise in the right sided cardiac pressures. Eventually, the acute PFO provided a necessary outflow tract for right sided pressure overload

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease