Whole genome sequencing identifies multiple loci for critical illness caused by COVID-19

Critical illness in COVID-19 is caused by inflammatory lung injury, mediated by the host immune system. We and others have shown that host genetic variation influences the development of illness requiring critical care1 or hospitalisation2;3;4 following SARS-Co-V2 infection. The GenOMICC (Genetics of Mortality in Critical Care) study recruits critically-ill cases and compares their genomes with population controls in order to find underlying disease mechanisms. Here, we use whole genome sequencing and statistical fine mapping in 7,491 critically-ill cases compared with 48,400 population controls to discover and replicate 22 independent variants that significantly predispose to life-threatening COVID-19. We identify 15 new independent associations with critical COVID-19, including variants within genes involved in interferon signalling (IL10RB, PLSCR1), leucocyte differentiation (BCL11A), and blood type antigen secretor status (FUT2). Using transcriptome-wide association and colocalisation to infer the effect of gene expression on disease severity, we find evidence implicating expression of multiple genes, including reduced expression of a membrane flippase (ATP11A), and increased mucin expression (MUC1), in critical disease. We show that comparison between critically-ill cases and population controls is highly efficient for genetic association analysis and enables detection of therapeutically-relevant mechanisms of disease. Therapeutic predictions arising from these findings require testing in clinical trials.

A collaborative maternity dashboard (CoMaND) for the COVID-19 pandemic: a protocol for timely, adaptive monitoring of perinatal outcomes in Melbourne, Australia

BackgroundThe COVID-19 pandemic has resulted in a range of unprecedented disruptions to the delivery of maternity care globally and has been associated with regional changes in perinatal outcomes such as stillbirth and preterm birth. Metropolitan Melbourne endured one of the longest and most stringent lockdowns in 2020. This paper presents the protocol for a collaborative maternity dashboard project to monitor perinatal outcomes in Melbourne, Australia, during the COVID-19 pandemic. MethodsDe-identified maternal and newborn outcomes will be collected monthly from all public maternity services in Melbourne, allowing rapid analysis of a multitude of perinatal indicators. Weekly outcomes will be displayed as run charts according to established methods for detecting non-random signals in health care. A pre-pandemic median for all indicators will be calculated for the period of January 2018 to March 2020. A significant shift is defined as [≤] six consecutive weeks, all above or below the pre-pandemic median. Additional statistical analyses such as regression, time-series, and survival analyses will be performed for an in-depth examination of maternal and perinatal outcomes of interests. Ethics and DisseminationThis study has been registered as an observational study with the Australian and New Zealand Clinical Trials Registry (ACTRN12620000878976). Strengths and weaknesses of this study This project is the first clinician-led, multi-centre perinatal data collection system for metropolitan Melbourne. It complements the state government data collection, with the significant benefits of more timely and flexible reporting of outcomes, and granular detail on emerging areas of concern. The study relies on primary source coding of exposure and outcomes from each hospital that have not been internally validated during the study period. Data from private maternity hospitals, containing 25% of Melbourne births, are not available. This resource will support data-informed hospital pandemic responses through to the end of 2022.

Genetic association analysis of SARS-CoV-2 infection in 455,838 UK Biobank participants

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We investigated associations between rare genetic variants and seven COVID-19 outcomes in 543,213 individuals, including 8,248 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 14 interferon pathway genes in which rare deleterious variants have been reported in severe COVID-19 patients; (ii) 167 genes located in COVID-19 GWAS risk loci; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly browsable at https://rgc-covid19.regeneron.com.

Genetic mechanisms of critical illness in Covid-19

The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs1 and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.2 Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19.3 GenOMICC (Genetics Of Mortality In Critical Care, genomicc.org) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 x 10-12), within the gene encoding dipeptidyl peptidase 9 (DPP9), at chr12q24.13 (rs10735079, p =1.65 x 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), and at chr21q22.1 (rs2236757, p = 4.99 x 10-8) in the interferon receptor gene IFNAR2. Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 4.77 x 10-30). We identify potential targets for repurposing of licensed medications. Using Mendelian randomisation we found evidence in support of a causal link from low expression of IFNAR2, and high expression of TYK2, to life-threatening disease. Transcriptome-wide association in lung tissue revealed that high expression of the monocyte/macrophage chemotactic receptor CCR2 is associated with severe Covid-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms, and mediators of inflammatory organ damage in Covid-19. Both mechanisms may be amenable to targeted treatment with existing drugs. Large-scale randomised clinical trials will be essential before any change to clinical practice.

Thermoregulatory responses and hydration practices in heat-acclimatized adolescents during preseason high school football.

CONTEXT: Previous researchers have not investigated the thermoregulatory responses to multiple consecutive days of American football in adolescents. OBJECTIVE: To examine the thermoregulatory and hydration responses of high school players during formal preseason football practices. DESIGN: Observational study. SETTING: Players practiced outdoors in late August once per day on days 1 through 5, twice per day on days 6 and 7, and once per day on days 8 through 10. Maximum wet bulb globe temperature averaged 23 +/- 4 degrees C. PATIENTS OR OTHER PARTICIPANTS: Twenty-five heat-acclimatized adolescent boys (age = 15 +/- 1 years, height = 180 +/- 8 cm, mass = 81.4 +/- 15.8 kg, body fat = 12 +/- 5%, Tanner stage = 4 +/- 1). MAIN OUTCOME MEASURE(S): We observed participants within and across preseason practices of football. Measures included gastrointestinal temperature (T(GI)), urine osmolality, sweat rate, forearm sweat composition, fluid consumption, testosterone to cortisol ratio, perceptual measures of thirst, perceptual measures of thermal sensation, a modified Environmental Symptoms Questionnaire, and knowledge questionnaires assessing the participants' understanding of heat illnesses and hydration. Results were analyzed for differences across time and were compared between younger (14-15 years, n = 13) and older (16-17 years, n = 12) participants. RESULTS: Maximum daily T(GI) values remained less than 40 degrees C and were correlated with maximum wet bulb globe temperature (r = 0.59, P = .009). Average urine osmolality indicated that participants generally experienced minimal to moderate hypohydration before (881 +/- 285 mOsmol/kg) and after (856 +/- 259 mOsmol/kg) each practice as a result of replacing approximately two-thirds of their sweat losses during exercise but inadequately rehydrating between practices. Age did not affect most variables; however, sweat rate was lower in younger participants (0.6 +/- 0.2 L/h) than in older participants (0.8 +/- 0.1 L/h) (F(1,18) = 8.774, P = .008). CONCLUSIONS: Previously heat-acclimatized adolescent boys (T(GI) < 40 degrees C) can safely complete the initial days of preseason football practice in moderate environmental conditions using well-designed practice guidelines. Adolescent boys replaced most sweat lost during practice but remained mildly hypohydrated throughout data collection, indicating inadequate hydration habits when they were not at practice.