Alzheimer disease genetic risk factor APOE e4, and cognitive abilities in 111,739 UK Biobank participants

Background: the apolipoprotein (APOE) e4 locus is a genetic risk factor for dementia. Carriers of the e4 allele may be more vulnerable to conditions that are independent risk factors for cognitive decline, such as cardiometabolic diseases. Objective: we tested whether any association with APOE e4 status on cognitive ability was larger in older ages or in those with cardiometabolic diseases. Subjects: UK Biobank includes over 500,000 middle- and older aged adults who have undergone detailed medical and cognitive phenotypic assessment. Around 150,000 currently have genetic data. We examined 111,739 participants with complete genetic and cognitive data. Methods: baseline cognitive data relating to information processing speed, memory and reasoning were used. We tested for interactions with age and with the presence versus absence of type 2 diabetes (T2D), coronary artery disease (CAD) and hypertension. Results: in several instances, APOE e4 dosage interacted with older age and disease presence to affect cognitive scores. When adjusted for potentially confounding variables, there was no APOE e4 effect on the outcome variables. Conclusions: future research in large independent cohorts should continue to investigate this important question, which has potential implications for aetiology related to dementia and cognitive impairment

Genome-wide and Mendelian randomisation studies of liver MRI yield insights into the pathogenesis of steatohepatitis

Background A non-invasive method to grade the severity of steatohepatitis and liver fibrosis is magnetic resonance imaging (MRI) based corrected T1 (cT1). We aimed to identify genetic variants influencing liver cT1 and use genetics to understand mechanisms underlying liver fibroinflammatory disease and its link with other metabolic traits and diseases. Methods First, we performed a genome-wide association study (GWAS) in 14,440 Europeans in UK Biobank with liver cT1 measures. Second, we explored the effects of the cT1 variants on liver blood tests, and a range of metabolic traits and diseases. Third, we used Mendelian randomisation to test the causal effects of 24 predominantly metabolic traits on liver cT1 measures. Results We identified six independent genetic variants associated with liver cT1 that reached GWAS significance threshold (p<5x10-8). Four of the variants (rs75935921 in SLC30A10, rs13107325 in SLC39A8, rs58542926 in TM6SF2, rs738409 in PNPLA3) were also associated with elevated transaminases and had variable effects on liver fat and other metabolic traits. Insulin resistance, type 2 diabetes, non-alcoholic fatty liver and BMI were causally associated with elevated cT1 whilst favourable adiposity (instrumented by variants associated with higher adiposity but lower risk of cardiometabolic disease and lower liver fat) was found to be protective. Conclusion The association between two metal ion transporters and cT1 indicates an important new mechanism in steatohepatitis. Future studies are needed to determine whether interventions targeting the identified transporters might prevent liver disease in at risk individuals

Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort

Background: There is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon. Methods: Here we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth. Results: Neither genetic measure was associated with season or month of birth within the UKBB sample. Conclusions: As our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure

Predicting Cardiovascular Risk Factors from Retinal Fundus Photographs using Deep Learning

Traditionally, medical discoveries are made by observing associations and then designing experiments to test these hypotheses. However, observing and quantifying associations in images can be difficult because of the wide variety of features, patterns, colors, values, shapes in real data. In this paper, we use deep learning, a machine learning technique that learns its own features, to discover new knowledge from retinal fundus images. Using models trained on data from 284,335 patients, and validated on two independent datasets of 12,026 and 999 patients, we predict cardiovascular risk factors not previously thought to be present or quantifiable in retinal images, such as such as age (within 3.26 years), gender (0.97 AUC), smoking status (0.71 AUC), HbA1c (within 1.39%), systolic blood pressure (within 11.23mmHg) as well as major adverse cardiac events (0.70 AUC). We further show that our models used distinct aspects of the anatomy to generate each prediction, such as the optic disc or blood vessels, opening avenues of further research

A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years' experience; the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies

Objectives: The paediatric idiopathic inflammatory myopathies (IIMs) are a group of rare chronic inflammatory disorders of childhood, affecting muscle, skin and other organs. There is a severe lack of evidence base for current treatment protocols in juvenile myositis. The rarity of these conditions means that multicentre collaboration is vital to facilitate studies of pathogenesis, treatment and disease outcomes. We have established a national registry and repository for childhood IIM, which aims to improve knowledge, facilitate research and clinical trials, and ultimately to improve outcomes for these patients. Methods: A UK-wide network of centres and research group was established to contribute to the study. Standardized patient assessment, data collection forms and sample protocols were agreed. The Biobank includes collection of peripheral blood mononuclear cells, serum, genomic DNA and biopsy material. An independent steering committee was established to oversee the use of data/samples. Centre training was provided for patient assessment, data collection and entry. Results: Ten years after inception, the study has recruited 285 children, of which 258 have JDM or juvenile PM; 86% of the cases have contributed the biological samples. Serial sampling linked directly to the clinical database makes this a highly valuable resource. The study has been a platform for 20 sub-studies and attracted considerable funding support. Assessment of children with myositis in contributing centres has changed through participation in this study. Conclusions: This establishment of a multicentre registry and Biobank has facilitated research and contributed to progress in the management of a complex group of rare muscloskeletal conditions

Biobank quality management in the BBMRI.be network

From as early as 2005, different guidelines and quality standards covering biobank activities and sample handling methods have been developed to improve and guarantee the reproducibility of biomarker research. Ten years on, the BBMRI.be Quality working group wanted to gauge the current situation of these aspects in the biobanks of the BBMRI.be network. To this end, two online surveys were launched (fall 2017 and fall 2018) to the biobank quality managers in the BBMRI.be network to determine the status and setup of their current quality management system (QMS) and how their QMS and related practices have evolved over a 14 month time period. All biobanks addressed by the two surveys provided a complete response (12 and 13, respectively). A QMS was implemented in 85% of biobanks, with 4 standards emerging as primary basis. Supplementary guidelines were used, with a strong preference for the ISBER best practices for biobanks. The Standard Preanalytical Code-an indicator of the preanalytical lifecycle of a biospecimen impacting the downstream analysis results-was already implemented in 50% of the biobanks while the other half intends future implementation. To assess and maintain the quality of their QMS, 62% of biobanks used self-assessment tools and 71% participated in proficiency testing schemes. The majority of biobanks had implemented procedures for general and biobank specific activities. However, policies regarding the business and sustainability aspect of biobank were only implemented in a limited number of biobanks. A clear desire for a peer-review audit was expressed by 69% of biobanks, with over half of them intending to implement the recently published biobank standard ISO20387. Overall, the biobanks of the BBMRI.be network have actively implemented a solid quality approach in their practices. The implementation of ISO 20387 may bring further professionalization of activities. Based on the needs expressed in this survey, the Quality working group will be setting up an audit program for the BBMRI.be biobanks, to enhance, harmonize and streamline their activities. On the whole, the biobanks in the BBMRI.be network are able to substantially contribute to translational research, as a primary facilitator guaranteeing high quality standards and reproducibility

Constructing effective ethical frameworks for biobanking

This paper is about the actual and potential development of an ethics that is appropriate to the practices and institutions of biobanking, the question being how best to develop a framework within which the relevant ethical questions are first identified and then addressed in the right ways. It begins with ways in which a standard approach in bioethics – namely upholding a principle of individual autonomy via the practice of gaining donors’ informed consent – is an inadequate ethical framework for biobanking. In donating material to a biobank, the individual donor relinquishes a degree of control and knowledge over the way their material is used in large-scale and typically open ended projects; and the identifying nature of genetic material means that third parties have rights and interests which must be taken into account as well as those of the individual donor. After discussing the problems for informed consent in the biobanking context, the paper then considers three emerging alternative approaches which, broadly speaking, conceptualize the subject of biobanking ethics in communal or co-operative terms: one version sees participants in biobanking research as ‘shareholders’ whilst the other expands on the notion of participation to include the wider public beneficiaries of biobanking as ‘stakeholders’. It concludes by outlining a third view, on which the biobanking institution itself is conceived as an ethical subject whose defining function can do useful normative work in guiding and evaluating its activities