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

Strategic habitat restoration: Maximizing both ecological and social value in the Lower Duwamish River

Thesis (Master's)--University of Washington, 2014The Lower Duwamish River (LDR) estuary is an 11-mile stretch of river that contains the core of industrial activity in the Seattle area. As Seattle's only river, it is also habitat for many of the region's valued fish species. Over 150 years of development have polluted and degraded the river, and significant habitat restoration is now required under federal and state law. However, given the context of urban development and industrial activity, projects tend to be small and opportunistic, with limited ecological value. At the same time, the LDR is home to several underserved urban neighborhoods, and restoration projects have the potential to bring significant social value to these communities. In order to resolve the diverse ecological and social goals for the LDR, this study analyzed 10 plans in order to develop a conceptual model of the value of restoration. Six ecological metrics and eight social metrics were identified from this model, and multi-criteria decision analysis was used to combine the metrics into overall indices of ecological and social value. These metrics and indices were then calculated for 511 waterfront parcels in the LDR. Results show more variability with positive skewness in the ecological index, and a more normal distribution with higher average values in the social index. Spatial analysis revealed higher ecological value in the northern, industrial section of the LDR, with particular dependence on the existing habitat network. Social value was higher in the southern section and as the river passes through residential neighborhoods. Both the methodology and results of this study can inform site selection for future restoration projects in the LDR, in support of the goal that such projects maximize both ecological and social value

Maximizing ecological and social benefits of habitat restoration in the Lower Duwamish River: A spatial framework for site selection

Thesis (Master's)--University of Washington, 2014The Lower Duwamish River (LDR) estuary is an 11-mile stretch of river that contains the core of industrial activity in the Seattle area. As the city's only river, the LDR also provides important habitat for many of the region's valued fish and wildlife species. However, its long history of urban development and industrial activity has polluted and degraded the river, and significant habitat restoration is now required under federal and state law. Given the highly developed urban industrial setting of the LDR, habitat restoration projects tend to be small and opportunistic, with limited ecological value. At the same time, the LDR is home to several underserved urban neighborhoods, and restoration projects have the potential to bring significant social value to these communities. Maximizing this potential value together with ecological value requires a more strategic approach to restoration. Through a review of local and regional planning documents, I developed a list of community-defined characteristics that contribute to a restoration project's potential ecological and social value in the LDR. I then used these characteristics to explore the spatial distribution of potential restoration value in the river, creating a series of heat maps of potential value for each characteristic, and for overall potential ecological and social value. I developed six ecological metrics and eight social metrics, which I calculated for 511 waterfront parcels in the LDR. Results show more variability with positive skewness in the ecological index, and a more normal distribution with higher average values in the social index. Spatial analysis revealed higher ecological value in the northern, industrial section of the LDR, with particular dependence on the existing habitat network. Social value was higher in the southern section and as the river passes through residential neighborhoods. These results can inform site selection for future restoration projects in the LDR. Methodologies and results for individual metrics can be used to address project-specific objectives, while use of the complete collection can inform those restoration projects that seek to maximize overall ecological and social benefits in the LDR

A Magazine Spring 2017

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COVID-19 Host Genetics Initiative. A first update on mapping the human genetic architecture of COVID-19

The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.</p

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

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization 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