Multi-ancestry Mendelian randomization of omics traits revealing drug targets of COVID-19 severity

BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions. FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10(−4); OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10(−4); OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications. INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets. FUNDING: No

Kepler-21b: A 1.6REarth Planet Transiting the Bright Oscillating F Subgiant Star HD 179070

We present Kepler observations of the bright (V=8.3), oscillating star HD 179070. The observations show transit-like events which reveal that the star is orbited every 2.8 days by a small, 1.6 R_Earth object. Seismic studies of HD 179070 using short cadence Kepler observations show that HD 179070 has a frequencypower spectrum consistent with solar-like oscillations that are acoustic p-modes. Asteroseismic analysis provides robust values for the mass and radius of HD 179070, 1.34{\pm}0.06 M{\circ} and 1.86{\pm}0.04 R{\circ} respectively, as well as yielding an age of 2.84{\pm}0.34 Gyr for this F5 subgiant. Together with ground-based follow-up observations, analysis of the Kepler light curves and image data, and blend scenario models, we conservatively show at the >99.7% confidence level (3{\sigma}) that the transit event is caused by a 1.64{\pm}0.04 R_Earth exoplanet in a 2.785755{\pm}0.000032 day orbit. The exoplanet is only 0.04 AU away from the star and our spectroscopic observations provide an upper limit to its mass of ~10 M_Earth (2-{\sigma}). HD 179070 is the brightest exoplanet host star yet discovered by Kepler.Comment: Accepted to Ap

National Guidelines For The Management Of Pain In Older Adults

Consultation Paper- This guidance document reviews the epidemiology and management of pain in older people via a systematic literature review of published research. The aim of this document is to inform any health professionals in any care settings who work with older adults on best practice for the management of pain and to identify any gaps in the evidence which may require further research

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease

Food Cost Review, 1988

Food prices, as measured by the Consumer Price Index, increased 4.1 percent in 1988, the same increase as in 1987. But prices rose at a much higher rate in the second half of 1988 than in the first half due to the severe drought and other market factors. The prices farmers received for commodities, as measured by the farm value of USDA's market basket of foods, rose 3.6 percent. Farm value of foods had dropped in 2 of the previous 3 years. The farm value share of the food dollar spent in grocery stores was 30 percent, unchanged from 1987. The farm-to-retail price spread of USDA's market basket of foods rose 4.7 percent, partly reflecting higher prices of inputs used in handling, processing, and retailing foods

Food Cost Review, 1986

Food prices, as measured by the Consumer Price Index, increased 3.2 percent in 1986, compared with a 2.3-percent rise in 1985. The larger rise partly reflected a 4.3-percent increase in meat, poultry, and fish prices whereas prices declined slightly in 1985. The prices farmers received for commodities, as measured by the farm value of USDA's market basket of foods, declined 1.3 percent. This decline and a much larger one in 1985 brought the 1986 farm value of foods to the lowest value since 1979. The farm-value share of a dollar spent at foodstores fell to 30 percent from 31 percent in 1985. The farm-to-retail price spread of USDA's market basket of foods rose by 3.7 percent, partly reflecting higher food industry labor costs from rising employment. Higher advertising, packaging, and other food marketing expenses also contributed to the rise in the farm-to-retail price spread

Food Costs… From Farm to Retail in 1991

How much are food costs changing? Why? How much of the consumer food dollar goes to the farmer and how much to food processors and marketers? Because of great interest in these questions, Congress directed the U.S. Department of Agriculture (USDA) to regularly study them and to report its findings. This bulletin provides the answers, focusing on developments in 1991

Food Cost Review, 1987

Food prices, as measured by the Consumer Price Index, increased 4.1 percent in 1987, compared with a 3.2-percent rise in 1986. The larger rise reflected a 4.3-percent increase in prices of food bought in grocery stores for consumption at home compared with a 2.9-percent rise in 1986. The prices farmers received for commodities, as measured by the farm value of USDA's market basket of foods, rose 2.3 percent. Farm value of foods had dropped 8 percent the previous 2 years. The farm-to-retail price spread of USDA's market basket of foods rose by 6.2 percent, partly reflecting higher food industry labor costs from rising employment. Higher advertising, packaging, and other food marketing expenses also contributed to the rise in the farm-to-retail price spread