Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias

Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population

CAG repeat expansions in exon 1 of the AR gene on the X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with a variety of extra-neurological symptoms. The disease has a reported male prevalence of 1:30,303 or less, but the AR repeat expansion frequency is unknown. We established a pipeline, which combines the use of the ExpansionHunter tool and visual validation, to detect AR CAG expansion on whole-genome sequencing data, benchmarked it to fragment PCR sizing, and applied it to 74,277 unrelated individuals from four large cohorts. Our pipeline showed sensitivity of 100% (95% C.I. 90.8-100%), specificity of 99% (95% C.I. 94.2-99.7%), and positive predictive value of 97.4% (95% C.I. 84.4-99.6%). We found the mutation frequency to be 1:3,182 (95% C.I. 1:2,309-1:4,386, n=117,734) X chromosomes - ten times more frequent than the reported disease prevalence. Modelling using the novel mutation frequency led to estimate disease prevalence of 1:6,887 males, more than four times more frequent than the reported disease prevalence. This discrepancy is possibly due to underdiagnosis of this neuromuscular condition, reduced prevalence, and/or pleomorphic clinical manifestations

Where did it all go wrong? Implementation failure - and more - in a field experiment of procedural justice policing

Objectives: This paper presents the findings from a retrospectively conducted qualitative process evaluation to the Scottish Community Engagement Trial (ScotCET). The study explores the unanticipated results of a randomised field trial testing the effect of ‘procedurally just’ modes of road policing on public perceptions of police. The ScotCET intervention failed to produce the hypothesised results, producing instead significant, and unexplained, negative effects on key aspects of public perception. The present study seeks to examine, from the perspectives of officers implementing the experiment, what the impacts (intended or otherwise) of participation were. Methods: Group interviews were held within the ScotCET experiment ‘units’ to explore how officers had collectively interpreted and framed ScotCET, and responded as a group to its requirements/ demands. Nine groups were held over a 5 month period post experiment completion. Results: Findings indicate that communication breakdowns during the ScotCET implementation led to misunderstandings of its aims and objectives, and of the requirements placed on officers. Within a context of organisational reform and perceived organizational ‘injustice’, commonly cited aspects of police culture were invoked to facilitate officer non-compliance with aspects of the experimental intervention, leading to implementation failures, and, possibly, a diffuse negative effect on the attitudes and behaviours of experiment officers. Conclusions: Organizational structures and processes, and coercive top-down direction, are insufficient to ensure successful implementation of policing research, and, by implication, policing reforms, particularly those that demand alternative ways of ‘doing’ policing and ‘seeing’ citizens. Greater investment in organisational justice and encouraging openness to evidence-led knowledge is needed to promote change

Enhancing public trust and police legitimacy during road traffic encounters:Results from a randomised controlled trial in Scotland

Objectives This paper reports results from the Scottish Community Engagement Trial (ScotCET), devised to replicate the Queensland Community Trial (QCET). ScotCET was an RCT that tested the effects of ‘procedurally just’ policing on public trust and police legitimacy Methods A block-randomized (matched pairs) design, with pretest and posttest measures, was implemented in the context of road policing in Scotland. Participants were drivers stopped by police in December and January 2013/14 as part of Police Scotland’s ‘Festive Road Safety Campaign’. The experimental intervention comprised a checklist of key messages to include in routine roadside vehicle stops, and a leaflet for officers to give to drivers. Analysis proceeds via random effects regression models predicting latent variable measures of trust, satisfaction and legitimacy Results Contrary to expectations the intervention did not improve trust and legitimacy; rather, trust in the officers who made the stop, and satisfaction with their conduct fell in the test sites, relative to the controls, after implementation of the intervention. The intervention had no significant effect on general trust in the police, or on police legitimacy. Conclusions Results demonstrate the difficulty in translating experimental interventions across policing contexts, and challenge the notion that public perceptions may be improved through a simple, additive approach to the delivery and communication of procedural justice.</p

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.Peer reviewe

ClinVar data parsing

This software repository provides a pipeline for converting raw ClinVar data files into analysis-friendly tab-delimited tables, and also provides these tables for the most recent ClinVar release. Separate tables are generated for genome builds GRCh37 and GRCh38 as well as for mono-allelic variants and complex multi-allelic variants. Additionally, the tables are augmented with allele frequencies from the ExAC and gnomAD datasets as these are often consulted when analyzing ClinVar variants. Overall, this work provides ClinVar data in a format that is easier to work with and can be directly loaded into a variety of popular analysis tools such as R, python pandas, and SQL databases

Variant Score Ranker - a web application for intuitive missense variant prioritization

The correct classification of missense variants as benign or pathogenic remains challenging. Pathogenic variants are expected to have higher deleterious prediction scores than benign variants in the same gene. However, most of the existing variant annotation tools do not reference the score range of benign population variants on gene level. Here, we present a web-application, Variant Score Ranker, which enables users to rapidly annotate variants and perform gene-specific variant score ranking on the population level. We also provide an intuitive example of how gene- and population-calibrated variant ranking scores can improve epilepsy variant prioritization