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Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19

Publication: Nature Medicine

Liam Gaziano, Claudia Giambartolomei, Alexandre C. Pereira, Anna Gaulton, Daniel C. Posner, Sonja A. Swanson, Yuk-Lam Ho, Sudha K. Iyengar, Nicole M. Kosik, Marijana Vujkovic, David R. Gagnon, A. Patrícia Bento, Inigo Barrio-Hernandez, Lars Rönnblom, Niklas Hagberg, Christian Lundtoft, Claudia Langenberg, Maik Pietzner, Dennis Valentine, Stefano Gustincich, Gian Gaetano Tartaglia, Elias Allara, Praveen Surendran, Stephen Burgess, 
Jing Hua Zhao, James E. Peters, Bram P. Prins, Emanuele Di Angelantonio, Poornima Devineni, Yunling Shi, Kristine E. Lynch, Scott L. DuVall, Helene Garcon, Lauren O. Thomann, Jin J. Zhou, Bryan R. Gorman, Jennifer E. Huffman, Christopher J. O’Donnell, Philip S. Tsao, Jean C. Beckham, Saiju Pyarajan, Sumitra Muralidhar, Grant D. Huang, Rachel Ramoni, Pedro Beltrao, John Danesh, Adriana M. Hung, Kyong-Mi Chang, Yan V. Sun, Jacob Joseph, Andrew R. Leach, Todd L. Edwards, Kelly Cho, J. Michael Gaziano, Adam S. Butterworth, Juan P. Casas & VA Million Veteran Program COVID-19 Science Initiative

9 April 2021

Summary:

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, researchers conducted Mendelian randomization (MR) analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development.

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Survey of CAMHS clinicians about their experience of remote working: brief report

Publication: BJPsych Open

Bhardwaj A, Moore A, Cardinal RN, Bradley C, Cross L, Ford TJ

13 January 2021

The Covid-19 crisis necessitated rapid adoption of remote consultations across National Health Service (NHS) child and adolescent mental health services (CAMHS).

This study aimed to understand practitioners’ experiences of rapid implementation of remote consultations across CAMHS in one NHS trust in the east of England.

Data were collected through a brief questionnaire documenting clinicians’ experiences following remote delivery of services. The questionnaire began before ‘lockdown’ and focused on 102 assessment consultations as part of a planned move to virtual assessment.

As the roll-out of remote consultations was extended at lockdown, the researchers extended the questionnaire to include all remote clinical contacts (n = 202).

Despite high levels of initial concern, clinicians’ reports were positive overall; importantly, however, their experiences varied by team. When restrictions on face-to-face working are lifted, a blended approach of remote and face-to-face service delivery is recommended to optimise access and capacity while retaining effective and safe care.

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Birth weight, family history of diabetes and diabetes onset in schizophrenia

Publication: BMJ Open Diabetes Research & Care

Fernández-Egea E, Walker R, Ziauddeen H, Cardinal RN, Bullmore ET

28 January 2020

The prevalence of diabetes in schizophrenia is twice that in the general population, but there are few reliable predictors of which individuals will develop glucose dysregulation.

This research tested if abnormal birth weight (either too low or too high) and parental diabetes, both variables that can be ascertained in the clinic, can predict diabetes onset in patients with schizophrenia.

Researchers looked at electronic records of a cohort of 190 clozapine-treated patients (37% treated for more than 20 years) and Cox regression survival analysis (with any type of glucose dysregulation as the event) to account for differences in length of treatment before the event and age at clozapine treatment initiation.

Age at clozapine initiation, family history of diabetes and birth weight were significant predictors of glucose dysregulation onset, while gender was not.

Among individuals with 10 years of follow-up, 80% of those with both abnormal birth weight and a family history of diabetes developed diabetes compared with 56% with only abnormal birth weight, 40% with only a family history of diabetes and 20% in those with neither.

Since 48% of cases had at least one risk factor and 6% had both risk factors, there is a substantial proportion of patients for whom preventive strategies could be implemented.

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What can data trusts for health research learn from participatory governance in biobanks?

Publication: Journal of Medical Ethics

Richard Milne, Annie Sorbie, Mary Dixon-Woods

19 March 2021

Summary:

Researchers look at what we can learn from experiences of involving and engagement of members of the public and participants in the governance of large-scale biobanks.

Gene-environment correlations and causal effects of childhood maltreatment on physical and mental health: a genetically informed approach

Publication: The Lancet Psychiatry

Varun Warrier, Alex S F Kwong, Mannan Luo, Shareefa Dalvie, Jazz Croft, Hannah M Sallis, et al.

16 March 2021

Childhood maltreatment is associated with poor mental and physical health. However, the mechanisms of gene–environment correlations and the potential causal effects of childhood maltreatment on health are unknown. Using genetics, the researchers aimed to delineate the sources of gene–environment correlation for childhood maltreatment and the causal relationship between childhood maltreatment and health.

They did a genome-wide association study meta-analysis of childhood maltreatment using data from the UK Biobank, Psychiatric Genomics Consortium, Avon Longitudinal Study of Parents and Children, Adolescent Brain Cognitive Development Study and Generation R.

Family-based and population-based polygenic score analyses were done to elucidate gene–environment correlation mechanisms. The team used genetic correlation and Mendelian randomisation analyses to identify shared genetics and test causal relationships between childhood maltreatment and mental and physical health conditions.

This meta-analysis of genome-wide association studies identified 14 independent loci associated with childhood maltreatment. The researchers identified high genetic overlap among different maltreatment operationalisations, subtypes, and reporting methods.

Within-family analyses provided some support for active and reactive gene–environment correlation but did not show the absence of passive gene–environment correlation. Robust Mendelian randomisation suggested a potential causal role of childhood maltreatment in depression (unidirectional), as well as both schizophrenia and ADHD (bidirectional), but not in physical health conditions (coronary artery disease, type 2 diabetes) or inflammation (C-reactive protein concentration).

Childhood maltreatment has a heritable component, with substantial genetic correlations among different operationalisations, subtypes, and retrospective and prospective reports of childhood maltreatment.

Family-based analyses point to a role of active and reactive gene–environment correlation, with equivocal support for passive correlation. Mendelian randomisation supports a (primarily bidirectional) causal role of childhood maltreatment on mental health, but not on physical health conditions. This study identifies research avenues to inform the prevention of childhood maltreatment and its long-term effects.

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Improving reporting standards for polygenic scores in risk prediction studies

Publication: Nature

Hannah Wand, Samuel A. Lambert, Cecelia Tamburro, Michael A. Iacocca, Jack W. O’Sullivan, Catherine Sillari, Iftikhar J. Kullo, Robb Rowley, Jacqueline S. Dron, Deanna Brockman, Eric Venner, Mark I. McCarthy, Antonis C. Antoniou, Douglas F. Easton, Robert A. Hegele, Amit V. Khera, Nilanjan Chatterjee, Charles Kooperberg, Karen Edwards, Katherine Vlessis, Kim Kinnear, John N. Danesh, et al

10 March 2021

Summary

This research is a perspective piece that provides a framework to promote the validity, transparency, and reproducibility of polygenic risk scores (PRS) by encouraging authors to detail the study population, statistical methods, and potential clinical utility of a published score.

Polygenic risk scores (PRSs), which often aggregate results from genome-wide association studies, can bridge the gap between initial discovery efforts and clinical applications for the estimation of disease risk using genetics.

However, there is notable heterogeneity in the application and reporting of these risk scores, which hinders the translation of PRSs into clinical care. Here, in a collaboration between the Clinical Genome Resource (ClinGen) Complex Disease Working Group and the Polygenic Score (PGS) Catalog, the researchers present the Polygenic Risk Score Reporting Standards (PRS-RS), in which they update the Genetic Risk Prediction Studies (GRIPS) Statement to reflect the present state of the field.

Drawing on the input of experts in epidemiology, statistics, disease-specific applications, implementation and policy, this comprehensive reporting framework defines the minimal information that is needed to interpret and evaluate PRSs, especially with respect to downstream clinical applications.

The researchers encourage researchers to deposit and share PRSs through the PGS Catalog to facilitate reproducibility and comparative benchmarking. By providing these criteria in a structured format that builds on existing standards and ontologies, the use of this framework in publishing PRSs will facilitate translation into clinical care and progress towards defining best practice.

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The Polygenic Score Catalog as an open database for reproducibility and systematic evaluation;

Publication: Nature Genetics

Samuel A. Lambert, Laurent Gil, Simon Jupp, Scott C. Ritchie, Yu Xu, Annalisa Buniello, Aoife McMahon, Gad Abraham, Michael Chapman, Helen Parkinson, John Danesh, Jacqueline A. L. MacArthur & Michael Inouye

10 March 2021

Summary

Researchers have led a report describing an important new set of reporting guidelines and an international open science database for polygenic risk scores, which are powerful genomic tools being increasingly used to predict disease outcomes and traits.

The Polygenic Score (PGS) Catalog is an open resource of published scores (including variants, alleles and weights) and consistently curated metadata required for reproducibility and independent applications.

The PGS Catalog has capabilities for user deposition, expert curation and programmatic access, thus providing the community with a platform for PGS dissemination, research and translation.

It promotes PGS reproducibility by providing a venue to annotate and distribute scores according to current exemplar reporting standards. As such, it allows users to reuse and evaluate PGSs, to firmly establish their predictive ability and facilitate further investigations of clinical utility.

  • Visit the PGS Catalog website: https://www.PGSCatalog.org

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Modifiable Lifestyle Factors and Risk of Stroke

Publication: Stroke Aha

Eric L. Harshfield, Marios K. Georgakis, Rainer Malik, Martin Dichgans, Hugh S. Markus

4 February 2021

Summary

Assessing whether modifiable risk factors are causally associated with stroke risk.

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Linked electronic health records for research on a nationwide cohort including over 54 million people in England

Publication: MedRxiV

Angela Wood, Rachel Denholm, Sam Hollings, Jennifer Cooper, Samantha Ip,  Venexia Walker, Spiros Denaxas, Ashley Akbari, Jonathan Sterne, Cathie Sudlow, Rachel Denholm, Sam Hollings, Jennifer Cooper, Samantha Ip, Venexia Walker, Spiros Denaxas, Amitava Banerjee, William Whiteley, Alvina Lai, Rouven Priedon, Cathie Sudlow, Lynn Morrice, Debbie Ringham, Suzannah Power, Lynn Laidlaw, Michael Molete, John Walsh, Garry Coleman, Cath Day, Elizabeth Gaffney, Tim Gentry, Lisa Gray, Sam Hollings, Richard Irvine, Brian Roberts, Estelle Spence, Janet Waterhouse

23 February 2021

Summary:

A new population-wide health data resource to accelerate research on COVID-19 and cardiovascular disease in England.

This work has been led by the CVD-COVID-UK consortium in partnership with NHS Digital. The CVD-COVID-UK consortium is a collaborative group of more than 130 members across 40 institutions working to understand the relationship between COVID-19 and cardiovascular diseases. The consortium is managed by the British Heart Foundation (BHF) Data Science Centre, led by Health Data Research UK.

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Plant foods, dietary fibre and risk of ischaemic heart disease in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Publication: International Journal of Epidemiology

Aurora Perez-Cornago , Francesca L Crowe, Paul N Appleby, Kathryn E Bradbury, Angela M Wood, Marianne Uhre Jakobsen, Laura Johnson, Carlotta Sacerdote, Marinka Steur, Elisabete Weiderpass, Anne Mette L Würtz, Tilman Kühn, Verena Katzke, Antonia Trichopoulou, Anna Karakatsani, Carlo La Vecchia, Giovanna Masala, Rosario Tumino, Salvatore Panico, Ivonne Sluijs, Guri Skeie, Liher Imaz, Dafina Petrova, J Ramón Quirós, Sandra Milena Colorado Yohar, Paula Jakszyn, Olle Melander, Emily Sonestedt, Jonas Andersson, Maria Wennberg, Dagfinn Aune, Elio Riboli, Matthias B Schulze, Emanuele di Angelantonio, Nicholas J Wareham, John Danesh, Nita G Forouhi, Adam S Butterworth, Timothy J Key

3 March 2021

Summary

Epidemiological evidence indicates that diets rich in plant foods are associated with a moderately lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre.

This study found that higher intakes of fruit and vegetables combined, total fruit, bananas, nuts and seeds, total fibre, fruit and vegetable combined fibre and fruit fibre are associated with a lower risk of IHD, of small magnitude.

To the best of the researchers’ knowledge, this is the largest prospective study looking at major plant foods, their subtype, and dietary fibre in relation to IHD risk including incident IHD cases and death from IHD.

As with other observational studies, the associations reported may be subject to residual confounding, and whether these small associations are causal remains unclear.

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