Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and 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. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Comrades! Lives of Australian Communists

This collection of biographies of 100 Australian communists celebrates a century of the Communist Party of Australia (CPA). The CPA started small, on 30 October 1920, but its members' dedication and the course of world events made it a national, even international, force. They worked on the wharves, building sites, railways" in factories, mines, shops and hospitals. Others were novelists, playwrights, filmmakers, singers and lawyers. Many were union officials" one was Australia's only Communist Member of Parliament. Some were seared by World War, Depression, or the Cold War. Others were propelled by the social movements of the sixties and seventies. What drew them together was their opposition to the global dominance of capitalism, their desire for industrial and social justice, and the impulse to escape religious orthodoxy and class and gender privilege.Communists dared to think about a world without war, without divisions of race and class" of a society based on cooperation and shared wealth, and an economy run for the people. They believed that ordinary people, working together, could change the world.The CPA was the first party to oppose the White Australia policy, to stand up against fascism, and to fight for Aboriginal rights. Its members imposed the world's first Green Bans, and they helped build hundreds of social movement organizations though which people fought to have their say in the country's future. The books, plays, films and songs created by its members helped create a uniquely Australian culture. Many were subjected to surveillance and repression by Australian political police, discrimination at work, and constant public attacks. Few were ever acknowledged in history books or the media. To mark the centenary of the Communist Party of Australia, the SEARCH Foundation, in association with the Australian Society for the Study of Labour History, is compiling short biographies of Australian communists. This selection of 100 will be supplemented by many more on the SEARCH website (www.search.org.au

From equal pay to overcoming undervaluation : the Australian National Pay Equity Coalition 1988-2011

Australian feminists have struggled to define the International Labour Organisation’s Equal Remuneration Convention’ goal of gender pay equity and find a platform for achieving it. Approaches based on discrimination, or a male comparator, have proved unworkable. Networking nationally and internationally, the National Pay Equity Coalition (1988–2011) formulated many submissions to industrial tribunals and parliamentary inquiries. Early interventions argued the disadvantages to women of the decentralisation of bargaining in the 1990s, but following the failure of discrimination-based cases, this focus shifted. National Pay Equity Coalition submissions came to define the gender gap, not as one between women and male comparators, but as a recognition gap. They argued that indicators of a history of gender-based undervaluation should lead to a bias-free work value assessment. Bias lay in the distance between actual job demands and their characterisation in classification descriptions. It could be redressed by fuller recognition of the work value of feminised service roles. This approach to the recognition and remedy of undervaluation informed the 1998 NSW Pay Equity Inquiry and the NSW Equal Remuneration Principle, but is not recognised in federal labour law. No Equal Remuneration Principle yet applies in the federal jurisdiction which since 2009 has governed most Australian wage setting amidst growing social inequality