HDHL EpiBrain: Epigenetic effects of B-vitamins on brain health throughout life

Lead Research Organisation: University of Ulster
Department Name: Sch of Biomedical Sciences

Abstract

What's already known in this research area: Folic acid and closely related vitamins (vitamin B12, vitamins B6 and riboflavin) are critical for brain health throughout life. Low intakes of these nutrients may impact adversely on brain development in early life and brain function in later life. In early life, folic acid supplements are recommended for women who are trying to become pregnant and during the first 12 weeks of pregnancy in order to reduce the risk of neural tube defects (NTDs) including spina bifida. Apart from preventing NTDs, however, folic acid intake of mums during pregnancy appears to be associated with better cognitive performance in the child, but this aspect is still under investigation by scientists worldwide. The link between nutritional factors such as folic acid in mums during pregnancy and brain health in the child may be explained by 'Epigenetics'. This is the study of processes (such as DNA methylation) that alter our genes by switching them on and off, and we now know that diet can have a major influence on these genetic processes. These changes to our genes happen throughout the lifecycle, from the time of conception, through pregnancy, childhood, middle age and old age.

What EpiBrain will address: In order to support health improvement strategies, both for mothers during pregnancy and their babies on one hand, and for adults as they age on the other, we need a better understanding of how folic acid and related B vitamins influence specific genes related to brain development in the child and cognitive function in older adults. This is the overall purpose of the EpiBrain project.

How this will be achieved: The EpiBrain project will bring together research teams from the UK Canada and Spain who have strong expertise in nutrition and epigenetics and a track record of working successfully together. Our work will use 'epigenome-wide association studies' or EWAS, an approach that involves rapidly scanning complete sets of DNA to find epigenetic marks linked with health. This approach is necessary to more fully explore the biological basis explaining the impacts of maternal folic acid supplementation in pregnancy on brain development in the child, and interventions with B vitamins to improve cognitive function in later life. We will conduct new epigenetics analysis on stored samples from studies previously conducted by our research teams in pregnancy and older age. Dietary, nutritional and epigenetic data will be linked with cognitive function measurements in children and older adults. Brain function assessment will also include neuroimaging data using state-of-art magnetoencephalography (MEG) conducted in early and late life on our study participants, providing a direct measure of brain activity.

Why the results of the EpiBrain project are important: The EpiBrain project will lead to improved understanding of the role of folic acid and other B vitamins, their epigenetic effects and brain function in childhood and older age, with expected results anticipated to provide scientific substantiation to support nutritional strategies for sustaining better brain health through the lifespan. This project is very timely because of potential imminent changes in fortification and supplementation policies. The implementation of mandatory food fortification for NTD prevention is currently being debated at national levels in the UK and Ireland, while the team in Canada is working on challenges and solutions for the generating guidelines in relation to the amount of folic acid to incorporate into folic acid supplements for pregnant women. The EpiBrain project provides a unique opportunity for a truly transnational collaboration to study the potential effects of folic acid (that may be mediated by Epigenetics) on brain health throughout the lifecycle.

Technical Summary

Low dietary and biomarker status of folate and interrelated B vitamins (methyl donor nutrients) are known to lead to perturbations in one carbon (1C) metabolism that can impact adversely on brain development in early life and brain function in later life. Better maternal folate status in pregnancy is however associated with improved cognition in the offspring, whilst optimal folate and related B vitamin status may prevent cognitive decline in later life. The biological mechanisms explaining these relationships may involve DNA methylation of epigenetically-controlled genes related to brain development and function. A better understanding of the mechanisms linking relevant B vitamins and the epigenome with brain health at critical stages of the lifecycle is necessary to support evidence-based health improvement strategies. The EpiBrain project aims to investigate the nutrition-epigenome-brain relationship through the lifespan with a focus on methyl donor nutrients and their related epigenetic effects in relation to brain outcomes. We will conduct new epigenetics analysis on stored samples and access data from existing well characterised cohorts, both prospective studies (maternal-offspring pairs) and randomised controlled trials in pregnancy and older age. Genomic DNA extracted from maternal, child and older adult blood samples will be analysed for differentially methylated regions by genome-wide methylation analysis (850k microarray). Dietary, nutrient biomarker and epigenetic data will be linked with cognition in children and older adults. Brain function assessment will also include neuroimaging data using state-of-art magnetoencephalography (MEG) conducted in early and late life on B-vitamin trial participants to study the effects of methyl donor nutrients on neurological functioning. The EpiBrain project will provide scientific substantiation to support nutritional strategies for sustaining better brain health through the lifespan.

Planned Impact

Our proposal aligns closely with the JPI HDHL vision to support high-quality, translational, collaborative research and addresses the specific aim of this call, to further understanding of diet-epigenome relationships and their effect on human health across the lifespan. The proposed research focuses on methyl donor nutrients and their related epigenetic effects in relation to brain outcomes. We anticipate that results will contribute valuable data to help develop effective targeted nutritional strategies to promote better brain health throughout the lifespan and that the project overall will result in important societal impacts.

Health Impacts
The proposed research is well aligned with the goal of promoting health and wellness across the life span in global populations. The benefits of folic acid fortification in relation to the prevention of neural tube defects are well established however the role of folate and related B-vitamins on other key health outcomes, particularly neurodevelopment and brain function are less well understood but are suggested to be mediated by 1-carbon related epigenetic mechanisms. We plan to investigate these associations and in particular whether the epigenetics related to brain function in early life are also related to cognitive function in later life, and how these relationships are impacted by dietary intake and biochemical B-vitamin status. The current proposal thus offers a unique opportunity to investigate these associations in populations (Canadian, British and Spanish) with very different exposures to folate and related methyl nutrients thus providing novel data to help advance our understanding in this important research area across the global intake range. The findings will provide scientific substantiation to support intervention strategies for sustaining better health and preventing disease across the lifespan and align with a recent call from the European Food Safety Authority (EFSA) that prioritised the need for interdisciplinary collaboration and a targeted exploitation of available human epidemiological and clinical data to investigate the association between epigenetic changes and health effects. In their report outlining a 'A Cross-Council vision for Food, Nutrition and Health research' the Research Councils in the UK reported that many of the mechanisms underpinning the effects of food and nutrition on long-term health were under-investigated and called for multidisciplinary partnerships to deliver a robust and authoritative evidence base crucial to the development of healthier food products, optimisation and stratification of dietary guidelines, and determination of effective intervention strategies. https://mrc.ukri.org/documents/ pdf/cross-council-fnh-bk-26-march-2015/. It is envisaged the proposal will make a significant contribution to the evidence base for the European commission framework programme for research and innovation (Horizon 2020) 'Societal Challenges' relating to: 'Improving understanding of the determinants of health and disease prevention' and the European Innovation Partnership Strategic Implementation Plan on active and healthy ageing for: 'Prevention of functional decline, both physical and cognitive, in older people.

Societal and other impacts
EpiBrain brings together researchers with expertise in nutrition, epigenetics and neurodevelopment to engage in diet and health research at an international level.
It will establish a critical mass of expertise in this research area, allowing for excellent science and sharing of innovative approaches and infrastructures, and the data gathered will be made available to the wider research community.
A highly relevant aspect of EpiBrain will be to provide stakeholders, policy-makers, influencers and healthcare regulatory bodies at national and international levels with up-to-date and easily adaptable scientifically robust. recommendations for evidence-based action.
 
Description At the 13th Federation of European Nutrition Societies (FENS) conference, October 2019, in Dublin, Ireland, Dr Aoife Caffrey from UU presented findings from the Folic Acid Supplementation during the Second and Third Trimesters (FASSTT) Trial on "Maternal folate nutrition and offspring brain health", for which she received the DSM Bright Science Award for Innovative PhD research. Furthermore, Dr Kristina Pentieva from UU presented on "Maternal folic acid supplementation and offspring health: are there benefits beyond NTD?" as part of the Nutrition Innovation Centre for Food and Health (NICHE) symposium.
First Year Of Impact 2019
Sector Agriculture, Food and Drink,Education,Healthcare
Impact Types Societal

 
Description Prof Helene McNulty: Member of the European Advisory Board for Nestlé Nutrition Institute: Infant & Toddler Nutrition
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
Impact Prof Helene McNulty was a Member of the European Advisory Board for Nestlé Nutrition Institute: Infant & Toddler Nutrition (2015-2018)
 
Description Prof Helene McNulty: Member of the Northern Ireland Clinical Trials Unit (NICTU) Advisory Group
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
URL http://www.nictu.hscni.net/about-us/
 
Description Prof Helene McNulty: Member of the Public Health Nutrition Sub-Committee, Food Safety Authority of Ireland
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Prof Helene McNulty is currently a Member of the Public Health Nutrition Sub-Committee, Food Safety Authority of Ireland (2012-)
 
Title Development of Language Task Response Tool for use in Magnetoencephaology 
Description Our studies on children born to mothers who received folic acid supplementation in trimesters 2 and 3 of pregnancy have shown that these children perform better in standardised tests of verbal reasoning and other language tasks using standardised psychology tests such as WPPSSI. In order to gain greater insight into the biological underpinnings of this improved brain function, we wished to try and identify and quantitate and differences in brain activity between children in the placebo and folic acid supplement groups using a physical device. With colleagues in brain imaging and in collaboration with researchers at Aston University, we adapted existing computer-based tests to allow their use in a magnetoencephalography setting, which required substantial adaptation of both the questions and the format of delivery 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2019 
Provided To Others? No  
Impact The work has led to a number of exciting findings in terms of differences in brainwave activity in the placebo versus control children as measured by the superconducting quantum interference devices (SQUIDs) in the MEG, which can quantify changes in real-time in a non-invasive and relatively child-friendly setting. These results are currently being written up for submission as a further scientific paper by team members 
 
Title To determine whether taking folic acid during the later stages of pregnancy has any beneficial effects of the cognitive development and growth of the offspring 
Description The Trial has shown, using a variety of measures including clinical psychology tools, brain imaging, cognitive assessment, biomarker evaluation and epigenetic analysis, that continued supplementation of pregnant mothers beyond the first trimester (current recommendations in UK) has positive impacts on the offspring psychosocial and cognitive development. Through our champions on the FSA Ireland (McNulty) and European FSA (Pentieva) Committees this evidence is contributing to ongoing consultation on food fortification with folic acid. Through follow-on funding from the HDL/BBSRC we are now extending this work to look at epigenetic correlates of b-vitamin intervention in different countries as well as at different stages of the life course (see further funding section). 
Type Preventative Intervention - Nutrition and Chemoprevention
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2018
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Consultation on food fortification with folic acid in the UK is still on-going, but the results of our Trial have been reported in high-ranking journals in our respective fields as evidenced in the Publications attributed to the award 
URL http://www.bristol.ac.uk/integrative-epidemiology/epigenetics-social-science-network/research-projec...
 
Title CandiMeth- a software tool for quantifying and visualising DNA methylation changes 
Description DNA methylation microarrays are widely used in clinical epigenetics and are often processed using R packages like ChAMP or RnBeads by trained bioinfomaticians. However, looking at specific genes requires bespoke coding which wet-lab biologists or clinicians are not trained for. This leads to high demands on bioinfomaticians, who in turn may lack insight into the specific biological problem. We therefore wished to develop a tool for mapping and quantification of methylation differences at candidate genomic features of interest, without using coding, to bridge this gap. We therefore generated the workflow CandiMeth (CANDIdate METHylation) in the web-based environment Galaxy. CandiMeth takes as input any table listing differences in methylation generated by either of the popular R-based packages above and maps these to the human genome. A simple interface then allows the user to query the data using lists of gene names. CandiMeth generates 1)Tracks in the popular UCSC genome browser with an intuitive visual indicator of where differences in methylation occur between samples, or groups of samples 2) Tables containing quantitative data on the candidate regions, allowing interpretation of significance. In addition to genes and promoters, CandiMeth can analyse methylation differences at LINEs and SINEs. Cross-comparison to other open-resource genomic data at UCSC facilitates interpretation of the biological significance of the data and the design of wet lab assays to further explore methylation changes and their consequences for the candidate genes. CandiMeth allows rapid, quantitative analysis of methylation at user-specified features without the need for coding and is freely available through Github 
Type Of Technology Webtool/Application 
Year Produced 2020 
Open Source License? Yes  
Impact The software has been used in a number of our published papers (many listed against this award), done in collaboration with colleagues from a range of disciplines, and is empowering those in the life sciences to carry out their own analyses of epigenetic alterations without the need for extensive bioinformatics support. 
URL https://github.com/sjthursby/CandiMeth
 
Description Ms Maria Fernanda Mujica-Coopman: presentation at 12th International Conference on One Carbon Metabolism, B Vitamins and Homocysteine, Spain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Ms. Maria Fernanda Mujica-Coopman (PhD Researcher), "Early maternal methyl nutrient concentrations and their relationship with DNA methylation of fetal growth and obesity-related genes in the offspring: results from the Alberta Pregnancy Outcomes and Nutrition (APrON) study", 12th International Conference on One Carbon Metabolism, B Vitamins and Homocysteine, Spain, 9th-13th June 2019
Year(s) Of Engagement Activity 2019
 
Description Prof Colum P Walsh: presentation at BC Children's Hospital Research Institute, Canada 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Prof Column Walsh, "EpiFASSTT: Epigenetic effects on children's psychosocial development in a randomised trial of Folic Acid Supplementation in Second and Third Trimester", BC Children's Hospital Research Institute, Canada, 22 March 2019
Year(s) Of Engagement Activity 2019
 
Description Prof Helene McNulty: Chair of the Epigenetics in Health and Disease Workshop, April 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Prof Helene McNulty was invited to Chair the Epigenetics in Health and Disease Workshop: Current views and interdisciplinary research through the life-course, Ulster University, Coleraine, April 2019
Year(s) Of Engagement Activity 2019
 
Description Prof Helene McNulty: Co-chair of the Executive Committee, 13th FENS European Nutrition Conference, Oct 2019 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prof Helene McNulty was the Co-Chair of the Executive Committee, 13th FENS European Nutrition Conference, Dublin 15-18 Oct 2019
Year(s) Of Engagement Activity 2019
URL http://www.fens2019.org/welcome/letter-from-co-chairs/
 
Description Prof Helene McNulty: presented at the 12th International Conference on One Carbon Metabolism, B Vitamins and Homocysteine, Spain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prof Helene McNulty, "Achieving Optimal Folate Status for Health (in European Populations): natural food folates versus folic acid", 12th International Conference on One Carbon
Metabolism, B Vitamins and Homocysteine, Spain, 9th-13th June 2019
Year(s) Of Engagement Activity 2019
 
Description Prof Kristina Pentieva: presentation at the FENS 2019 conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prof Kristina Pentieva presented 'Maternal folic acid supplementation and offspring health: are there benefits beyond NTD?' at the Nutrition Innovation Centre for Food and Health (NICHE) Symposium at FENS 2019 conference.
Year(s) Of Engagement Activity 2019
URL https://app.oxfordabstracts.com/events/696/program-app/submission/133490
 
Description Prof Yvonne Lamers: presented at the 12th International Conference on One Carbon Metabolism, B Vitamins and Homocysteine, Spain 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prof Yvonne Lamers, "From possible inadequacy to excess - discrepancy in folate status and folic acid intake of pregnant women across countries and supplementation guidelines", 12th International Conference on One Carbon Metabolism, B Vitamins and Homocysteine, Spain, 9th-13th June 2019
Year(s) Of Engagement Activity 2019