Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

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

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 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

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

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 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

The Australian Criminal Code: Time for some changes

Ian Leader-Elliotthttp://www.federallawreview.com.au/Current_Issue/volume37No2.ht

Sentencing by weight: proposed changes to the Commonwealth Code's serious drug offences

Major increases in the punishment for Criminal Code offences of trafficking, commercial cultivation and manufacture of controlled drugs are under consideration by the Commonwealth government. The proposed increases would be effected by new model schedules of controlled drugs which would have two effects. First, the model schedules would extend the penalties of imprisonment for life and imprisonment for 25 years to a range of substances that are currently the subject of comparatively minor, regulatory penalties. Secondly, they would extend the penalties of imprisonment for life and imprisonment for 25 years to far smaller quantities of the existing class of controlled drugs. The model schedules are proposed as a model for uniform adoption in all Australian jurisdictions. They have already been adopted in South Australia. This article discusses the Commonwealth proposals with particular reference to the lack of evidence or argument to justify the dramatic increases in penalties proposed.Ian Leader-Elliotthttp://sites.thomsonreuters.com.au/journals/2012/09/21/criminal-law-journal-update-october-2012

Benthamite reflections on codification of the general principles of criminal liability: Towards the panopticon

Chapter 2 of the Australian Commonwealth Criminal Code codifies the general principles of criminal liability. All federal criminal offences, whether or not they appear in the substant6ive chapters of the Code, are subject to its provisions. Chapter 2 is based on article 2 of the American Model Penal Code and the equivalent general part of the UK Draft Criminal Code. It is, however, a more completely articulated statement of the elements of liability than either of its predecessors. This paper examines the relationship between physical and fault elements in chapter 2. It takes a Benthamite view of its provisions. Though chapter 2 was conceived as a legislative restatement of common law principles of criminal justice it can be expected to play a more significant role as a manual of instructions for the expression of legislative intentions. Chapter 2 enables the legislature to reclaim from courts the authority to define the grounds of criminal liability. There remain, however, areas of uncertainty resulting from the mismatch between the articulate clarity of most chapter 2 provisions and others that envisage the exercise of unstructured judicial discretion. Two issues in particular are discussed: liability for ulterior intentions and the effect of error or ignorance of law on criminal responsibility. The paper proposes enactment of a defense of reasonable mistake of law as a supplement to chapter 2. It concludes with an expression of hope that Australian criminal law theory might be based on a more unified consideration of legisprudence and common law

Instinctive Synthesisers in the High Court

Ian Leader-Elliot

Faultlines Between Guilt and Punishment in Australia's Model Criminal Code

Ian Leader-Elliotthttp://trove.nla.gov.au/work/3531308

The Commonwealth Criminal Code: An introduction to the general principles

Overview of the Commonwealth Criminal code - particular emphasis to Part 2.2 'Elements of an Offence ' - issues in the jurisprudence of criminal responsibility - fault and presumptions of fault - fault and grades of culpability - recklessness and negligence in the Criminal Code - strict liability and negligence in the Criminal Code - the perils of disunity in matters of general principle