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

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Molecular identification of the precise geographic origins of an invasive shrimp species in a globally significant Australian biodiversity hotspot

This report details the first detection of invasive freshwater shrimp in the south-west of Western Australia, a region recognised for its biodiversity and the vulnerability of its endemic species. The species was detected as part of biosecurity surveillance of Perth’s freshwater lakes. The introduced specimens were tentatively identified morphologically as Caridina indistincta, and then confirmed by molecular analysis as “species B” of that taxon, part of a species-complex native to eastern Australia. Phylogeographic analyses were then used to narrow down the likely source population to a small area of south-eastern Queensland, over 3500 kms across the continent from the invasion sites. The potential source area is heavily involved in the trade in freshwater species for aquaria and recreational fish stocking. This information will help in identifying the precise invasion vector and could thus allow more targeted management measures to prevent future imports of exotic aquatic invasive species.No Full Tex

Perinecrotic Hypoxia Contributes to Ischemia/Reperfusion-Accelerated Outgrowth of Colorectal Micrometastases

Ischemia/reperfusion (I/R) is often inevitable during hepatic surgery and may stimulate the outgrowth of colorectal micrometastases. Postischemic microcirculatory disturbances contribute to I/R damage and may induce prolonged tissue hypoxia and consequent stabilization of hypoxia-inducible factor (HIF)-1α. The aim of this study was to evaluate the contribution of postischemic microcirculatory disturbances, hypoxia, and HIF-1α to I/R-accelerated tumor growth. Partial hepatic I/R attributable to temporary clamping of the left liver lobe induced microcirculatory failure for up to 5 days. This was accompanied by profound and prolonged perinecrotic tissue hypoxia, stabilization of HIF-1α, and massive perinecrotic outgrowth of pre-established micrometastases. Restoration of the microcirculation by treatment with Atrasentan and l-arginine minimized hypoxia and HIF-1α stabilization and reduced the accelerated outgrowth of micrometastases by 50%. Destabilization of HIF-1α by the HSP90 inhibitor 17-DMAG caused an increase in tissue necrosis but reduced I/R-stimulated tumor growth by more than 70%. In conclusion, prevention of postischemic microcirculatory disturbances and perinecrotic hypoxia reduces the accelerated outgrowth of colorectal liver metastases after I/R. This may, at least in part, be attributed to the prevention of HIF-1α stabilization. Prevention of tissue hypoxia or inhibition of HIF-1α may represent attractive approaches to limiting recurrent tumor growth after hepatic surgery

Genome-wide association analyses of risk tolerance and risky behaviors in over 1 million individuals identify hundreds of loci and shared genetic influences

Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated (|r^g| ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance

Identification of 371 genetic variants for age at first sex and birth linked to externalising behaviour

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility

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