NIHRDataInsights/HRCSData huggingface dataset:
Title: Assessing the pathogenicity, penetrance and expressivity of monogenic disease variants using large-scale population-based cohorts
Funder: Medical Research Council

Abstract: Combining genomic sequencing data from population and disease cohorts, this study will: 1. Critically evaluate which published genes in monogenic diabetes and developmental disorders should be reported as disease causing. 2. Generate minimum and age-dependent penetrance estimates for pathogenic genes. 3. Determine the phenotypic spectra for known pathogenic genetic variants in diabetes and developmental disorders. 4. Test the hypothesis that people in UK Biobank with confirmed monogenic variants have reduced penetrance due to a favourable genetic background. To achieve these objectives, we will: 1. Evaluate the relative enrichment or depletion of known and likely pathogenic SNVs, indels and CNVs in known monogenic disease genes (e.g. loss-of-function variants in monoallelic haploinsufficient developmental disorder genes) in UK Biobank compared with our two clinical cohorts (the DDD Study and Exeter monogenic diabetes study). We will perform extensive quality control of variants to evaluate analytical validity, including cross-platform comparisons, and also investigate potential somatic mosaicism in UK Biobank. 2. For confirmed pathogenic variants present in individuals in UK Biobank, we will evaluate the penetrance of the disease (based on phenotypes, age at recruitment, age of diagnosis where available, and affected status of parents). We will also evaluate age-related co-morbidities (e.g. frailty, dementia, CHD, etc.) and reduced penetrance of developmental phenotypes with age (e.g. educational attainment, fluid intelligence, height, BMI, etc). 3. We will construct relevant genome risk scores for e.g. T1D, T2D, height, BMI, intelligence, educational attainment, schizophrenia, etc. and evaluate whether individuals in UK Biobank, who have pathogenic monogenic variants but appear to have reduced penetrance or mild forms of disease, have a favourable genomic risk score that protects them from manifesting more severe forms of disease


Research activity codes: 4.4 POPULATION SCREENING
Health categories: GENERIC HEALTH RELEVANCE
Title: Using genetics to test the disease consequences of higher adiposity uncoupled from its adverse metabolic effects
Funder: Medical Research Council

Abstract: In this proposal we will improve understanding of the causal effects of two separate aspects of higher adiposity on common non-metabolic diseases - the excess weight, and the adverse metabolic consequences that normally accompany excess weight. We will use a novel genetic approach to separate the two components. In stage 1, we will use multivariate statistical approaches to identify additional "favourable adiposity" alleles using genotype data and adiposity related phenotype data from 100,000s of people. These alleles are those associated with higher adiposity but lower metabolic-disease risk. We will build a "favourable adiposity" genetic score from these alleles. We will also update the metabolically unfavourable "normal adiposity" genetic score. In stage 2, we will use abdominal MRI imaging data from four studies to understand the detailed fat distribution phenotypes of the "favourable adiposity" genetic score. These phenotypes will include subcutaneous, visceral, liver and pancreatic adipose and we will also assess lean mass. We will confirm associations with measures of insulin sensitivity. We will also use data from children to test whether or not the "favourable adiposity" genetic score is a proxy for favourable adiposity from early in life. In stage 3 we will characterise the non-metabolic diseases associated with higher adiposity in the UK Biobank. We anticipate taking forward approximately 20 diseases that are not clearly known consequences of the adverse metabolic effects of obesity. We will prioritise those diseases that have a sufficiently strong association with adiposity and with a large enough numbers of cases to have good statistical power for stage 4. In stage 4 we will use the metabolically "favourable adiposity" and "normal adiposity" genetic scores in a Mendelian Randomisation approach to test separately the effects of excess weight and the adverse metabolic effects on non-metabolic diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Transcription factor control of dynamic transitions within and beyond pluripotency
Funder: Medical Research Council

Abstract: Pluripotent cell identity is regulated by the transcription factors (TFs) Oct4, Sox2 and Nanog. However, the mechanisms by which TFs control self-renewal and differentiation remain elusive. Paradoxically, unipotent primordial germ cells also express these TFs. We will examine TF function through progression of pluripotent cells from a naïve to a formative state and into either the germline or the soma to reveal how PGRN TFs are repurposed during state transitions. Aim 1: How is pluripotency specified and lost in vivo? Single cell RNA-seq will identify specification defects in TF mutant embryos. We will assess NANOG variants and modulation of NANOG-responsive genes to compensate for Nanog in pluripotency specification. The mechanisms driving initial loss of pluripotency in vivo will be investigated and roles of pluripotency TFs in this process identified. Aim 2: How do TFs act in the maintenance and loss of naïve pluripotency in vitro? The involvement of direct NANOG target genes in ESC function will be assessed using a novel Cas9 approach that can potentially modulate positively and negatively regulated NANOG targets. Commitment from naïve pluripotency will be analysed using FACS-sorting of reporter lines and manipulation of the intracellular environment. Enhancer regulation by pluripotency TFs will be analysed by modified ChIP-seq techniques. Aim 3: What regulatory interactions determine the efficiency of entry to the germline? Formative pluripotent cells are competent for germline entry, a process enhanced by Otx2 mutation. We will investigate germline entry parameters and clarify Blimp1 operation. We will investigate whether entry to the human germline is increased in Otx2 mutants. This work will deliver mechanistic insight into pluripotent TF function. Application of such knowledge is crucial to design of robust protocols for in vitro differentiation of cells free from germline tumour-initiating cells for use in cell transplantation and drug discovery.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Causal mechanisms behind intergenerational transmission of nutritional choices and their association with metabolic risk indicators
Funder: Medical Research Council

Abstract: Low- and middle-income countries (LMICs) globally have undergone rapid urbanisation, and changes in demography and health behaviours. Whilst life expectancy at birth for many LMICs has improved, disease burden from non-communicable diseases, and years lived with disability have risen. In Sri Lanka, the setting for this proposed work, cardio-vascular disease is the leading cause of mortality, and an exponential increase in hospitalisations is seen for these diseases. High prevalence estimates of their risk factors, including hypertension (18-20%), dysglycaemia (14-20%) and obesity (9-36%) have been reported. Nutritional and dietary choices are key modifiable risk factors for both cardio-vascular disease and diabetes as well as their risk factors. They are not only genetically influenced behaviours but are also genetically correlated with metabolic risk indicators and known to be transmitted across generations. However, whether poor diet in parents leading to cardio vascular disease in the next generation is due to a direct behavioral impact or due to transmitted genetic factors and other family level variable like SES that can cause the association, is less understood. The main objective of the study is to examine the mechanisms by which parental diet impacts child nutritional choices and metabolic risk factors. The association may be environmental, due to the child growing up in a family who provide nutritional diet. Or the association may be due to passive gene-environment correlation whereby the child inherits a disposition for nutritional preference and for cardio-vascular disease but also the parent's dietary environment. The 'Children-of-Twins' design estimates the causal effects of parental on offspring traits while control for possible confounding familial effects. Using this design will help us understand the mechanisms underpinning intergenerational transmission of diet on cardio-vascular disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating human influences in systematic reviews and meta-analyses to improve the reliability and validity of evidence syntheses
Funder: Medical Research Council

Abstract: Systematic reviews underpin modern evidence-based medicine. However, there is an increasing body of research showing that they are susceptible to bias and are often not conducted well, despite the availability of established guidelines. I will investigate factors related to researcher influence within systematic reviews and develop resources to reduce bias or poor conduct in future reviews, increasing the quality and rigour of future systematic reviews. The effect that individuals may have on the conduct and conclusions of a systematic review is currently unknown. Researchers are responsible for making influential decisions at all stages of a review. Human influence over the conduct of a systematic review can occur due to author affiliation with the subject of investigation (bias or allegiance) but conversely review authors may be insufficiently skilled to take necessary efforts to perform a rigorous review. Such deviations from consistency and transparency, whether conscious or unconscious, can result in expensive outputs that fail to answer the review question. The full consequences to evidence-based medicine, of poor conduct in published reviews have not yet been explored. Methods: Rigorous methods to examine systematic review research will be combined with input from methodological experts. The proposed research includes: a) comprehensive systematic reviews and meta-regression team of human influences on systematic review outputs b) consultation and consensus with international methodological experts on i) the risks of ignoring team influences in systematic review, ii) solutions for systematic reviews and users via guidance c) highlighting the issues on the wider research agenda via a dedicated website This work will allow commissioners, researchers, publishers and policy makers to have greater confidence that conduct of systematic reviews, relied upon to inform decisions, is being scrutinised and that methods are evolving, as in primary research.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular basis of tRNA splicing by the TSEN complex in health and disease
Funder: Medical Research Council

Abstract: In eukaryotes, following RNA polymerase III transcription, the precursor tRNA (pre-tRNA) must be processed to produce mature tRNA. One such modification is excision of the intron present in 6% of the total pool of human tRNAs. This is carried out by the 5-subunit endonuclease complex TSEN/hClp1 which specifically cleaves the 5' and 3' splice sites using two independent active sites to liberate the intron. Loss of this regulated cleavage leads to aberrant tRNA fragment production, which sensitises neuronal cells to oxidative stress and increases p53-mediated cell apoptosis. This is relevant to brain development as mutations in subunits of TSEN/hClp1 are associated with early-onset of severe neurodegeneration such as prontocerebellar hypoplasia. Despite the apparent importance of regulated intron excision, the mechanism of action and regulation remains unclear. Recently, we have identified a novel regulatory mechanism where ATP binding regulates the specificity of the 5' splice site active site of TSEN/hClp1 in vitro. We hypothesise that TSEN/hClp1 may detect oxidative stress through changes in intracellular ATP concentrations to regulate apoptosis via tRNA fragment production in neurons, inappropriate activation of which leads to neurodegeneration. Therefore, we aim to understand the mechanism of pre-tRNA recognition and cleavage throughout the structure of unbound and substrate-bound TSEN/hClp1 complex, using cryo-EM and cross-linking/native mass spectrometry. This line of research would give unprecedented detail into the mechanism of tRNA splicing and provide the first study into the molecular basis of TSEN-associated neurodegeneration.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The Structural Biology of Amyloid Aggregation
Funder: Medical Research Council

Abstract: This 3-year project grant seeks to better understand amyloid fibril structure, and crucially, to understand how relevant fibrils of recombinant the dynamics and function and how these features contribute to cellular dysfunction and disease. Specifically, we will work with physicians with expertise in neurodegenerative and systemic amyloidosis, focussing on alpha-synuclein (involved in Parkinson's disease) and beta-2-microglobulin (involved in dialysis-related and systemic amyloidosis). Using cryo-EM and single particle image processing methods, together with ssNMR, we will reveal the structures of fibrils formed in vitro and purified ex vivo from patient samples. We we will also use mass spectrometry to understand the post-translational modification state of those ex vivo samples, allowing direct comparison to relevant in vitro fibrils. Building on a plethora of preliminary data that demonstrate the feasibility of the experiments proposed, we will thus address the following fundamental question: How do the structure(s) of amyloid fibrils generated in vitro compare with those formed in vivo? This will reveal new insights about these fascinating molecular assemblies and may inspire new opportunities to develop strategies to combat amyloid disease that harness the new structural insights gained.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Defining the gene regulatory mechanisms controlling the entry of human cells into naïve pluripotency
Funder: Medical Research Council

Abstract: Naïve and primed human pluripotent stem cells (hPSCs) differ substantially in molecular and functional properties that reflect their discrete developmental identities. Investigating naïve and primed hPSCs has enormous potential for uncovering the pathways that control different stages of pluripotency and for producing early developmental cell types that have sought after properties for biomedical applications. Although the reprogramming to an induced primed state has been studied in detail, much less is known about how naïve human pluripotency is acquired and stabilised. In response to this fundamental gap, we will determine the gene regulatory mechanisms that control the entry of human cells into naïve pluripotency. We have completed a genome-wide, loss-of-function screen (presented as preliminary data in the grant proposal) that identified unanticipated regulators of naïve hPSC reprogramming. Remarkably, 10 of the top 15 ranked genes encode the components of two complexes: PRC1.3 and SAGA. Our hypothesis is that PRC1.3 and SAGA recruit two distinct histone acetyltransferases (HATs) to activate transcription, and that these events are jointly required for driving effective cell state change. Our screen also identified Histone Deacetylase 2 (HDAC2) as a significant impediment to reprogramming, which suggests that HDAC2 counteracts HAT-mediated transcriptional activation during the initial phase of reprogramming. The central aim of this proposal is to investigate the newly identified barriers and facilitators of human naïve cell reprogramming and to develop a mechanistic understanding of how they act. This work will lead to important advances in understanding how human pluripotency is controlled, beyond that inferred from other species. Modulating the identified pathways will improve naïve cell production and open up new ways to deliver cell types with useful translational properties.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: MICA: Organ-on-a-chip models for safety testing of regenerative medicine products
Funder: Medical Research Council

Abstract: This project aims to support the ECE Hub by developing new robust, validated predictive models for the pre-clinical safety testing of regenerative medicine products. We focus on organ-on-a-chip approaches, and collaborate with one of the largest commercial company in the field, Emulate Inc., specifically to address the needs for reliability and control in a scaleable manner in new predictive models. We additionally engage with the regulatory bodies to support the integration of our predictive models into the regulatory framework for pre-clinical safety testing. Working directly with the Engineered Cell Environment Hub, our goals are to develop and validate new organ-on-a-chip models of each ECE Hub clinical focus area; liver, lung and joint. We will establish models within the Emulate platform technology (The Human Emulation Platform) phenotyping to ensure appropriate recapitulation of the organ on interest. We will carry out mechanistic safety testing in models, inputting drugs known to cause toxic effects in the organ in vivo, to ensure the organ-on-a-chip model can recapitulate that response. With appropriate validation in place, we will test some initial regenerative medicine products for the ECE Hub, working with the Edinburgh Phenotypic screening centre to align the drug libraries to those selected by the ECE Hub. We will also begin work on pathological models of organs within the organ-on-a-chip devices, to recapitulate situations in which the drug or product must be administered to a pathological organ.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: MICA: A partnership to extend the research utility of a source of real-world health data, the UK National Neonatal Research Database
Funder: Medical Research Council

Abstract: The National Neonatal Research Database (NNRD) is a dynamic relational database of extracts from the electronic patient records (EPR) of NHS neonatal unit admissions. We receive quarterly extracts over secure NHS N3 environment as a password protected .bak file of multiple tables reflecting groups of EPR entry screens, and identifier codes reflecting each table and episode of care. Neonatal care is delivered in a network model hence babies usually have multiple episodes across different hospitals. We remove identifiers and assign pseudonymised codes. We identify duplicate, missing, internally inconsistent and out-of-range entries. We check episode temporal consistency and hospital, provider and network codes, notifying neonatal units of potentially erroneous or missing entries. As each extract contains data on babies born within the last 5 years, corrections are incorporated progressively into the NNRD. With NHS Digital, we will automate the majority of these processes and publish detailed technical specifications. Supported by Bliss, we will identify and prioritise areas that researchers from different backgrounds, and parents, might wish to interrogate the NNRD (e.g. event rates, patient numbers, outcomes). The NNRD is managed in a MS SQL Server environment, hence can be used for automated reporting directly from data subsets. With SIA we will develop on-line analytical processing tools to enable standard queries to be run rapidly by researchers and parents. We will use applications such as IBM Cognos, MicroStrategy and Board MIT, basing initial development upon simulated data. We will also develop approaches to curate NNRD for future application of data-driven techniques such as selection of normalisation and clustering techniques (e.g. K-means, Dirichlet Process Gaussian Mixture Modelling), development of "smart" queries based on commonly utilised derived measures (e.g. birth weight Z-scores) and modelling time-dependent concepts (e.g. feeding patterns).


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Obesity and non-communicable disease in Malaysia: an imaging study of 6000 adults in the Malaysian Cohort Study
Funder: Medical Research Council

Abstract: Although BMI is frequently used in Malaysia to assess excess body fat, there have been no large-scale imaging studies with direct measurements of lean mass and regional fat masses which would allow us to understand reliably the relationship between body composition and disease outcomes in this population. Such an imaging study would inform public health guidance on the appropriate measures of excess body fat in this population, the ideal 'normal' range of these measures, and whether guidance should vary for the different ethnic groups in Malaysia; understanding differences between ethnic groups is particularly important given the ethnic diversity of the Malaysian populations. From 2006-2012, The Malaysian Cohort study - initiated by the Malaysian government - recruited 106,527 adults aged 35 years or over. Participants completed a lifestyle questionnaire, underwent physical measurements (including blood pressure, height, weight, hip and waist) and provided fasting blood and urine samples which were processed for long-term storage (half in -80C freezers and half in liquid nitrogen tanks). All participants are now being followed for health events. Baseline investigations included fasting blood glucose, fasting lipid profile, renal profile and full blood count, and re-surveys of a sample of the cohort are being conducted. In 6000 of The Malaysian Cohort participants, we will conduct whole-body Dual-energy X-ray Absorptiometry (DXA) imaging (which provides data on body composition, details of fat distribution and body fat percentage) using protocols established by the UK Biobank (a large cohort study run by the Nuffield Department of Population Health, University of Oxford). This imaging sub-study will significantly enhance this national biomedical resource by focusing on factors directly relevant to the consequences of obesity along with opening up opportunities for international collaboration.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE