Epigenetic effects of B-vitamins on brain health throughout life: scientific substantiation and translation of evidence for health-improvement strategies
|Partner Organization||Partner Country|
|Ulster University (UU)||United Kingdom|
|Health Sciences Universitat Rovira i Virgili (URV)||Spain|
|University of Calgary (UC)||Canada|
1. Overall project description
Low or imbalanced dietary and biomarker status of folate and interrelated B-vitamins (methyl donor nutrients) perturb 1-carbon metabolism, and adversely affect brain development in early life and brain function in later life. Human studies show that improved maternal folate status during pregnancy is 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 are not clear but 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 will lead to improved understanding of the role of 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. The consortium, including partners from Ulster University, Northern Ireland (UU), Health Sciences Universitat Rovira i Virgili, Spain (URV), University of Calgary, Canada (UC) and University of British Columbia, Canada (UBC), has strong expertise in B vitamin nutrition and epigenetics and a track record of working together across our institutions in Canada, UK and Spain.
Since the start of the transnational EpiBrain project, and despite the COVID-related delays and research curtailments, the team has made excellent progress and can report on novel findings and the development of a new software for quantitative methylation analysis.
The Folic Acid Supplementation during the Second and Third Trimesters (FASSTT) Trial from UU is the first study to test the effect of folic acid beyond the first trimester and has to date shared novel findings that find international interest and possible public health implications. Results from the FASSTT Trial showed that children of mothers who received folic acid supplementation in the second and third trimesters of pregnancy, compared to placebo, had higher overall cognition scores at 3 years of age and higher word reasoning scores at 7 years of age compared to the children of mothers in the placebo group. Follow-up of the children at 11 years also showed that language processing speed was higher in girls of mothers in the folic acid supplemented group compared to children of mothers in the placebo group. These findings have now been published, or are in press, in high-impact peer-reviewed medical and nutrition journals.
Further, Prof Colum Walsh and Dr Sara-Jayne Thursby from UU developed the user-friendly tool CandiMeth, which allows researchers with access to DNA methylation data from arrays to more easily look at specific genes and regions without having to write any code or use command line. The tool was developed particularly with colleagues such as those in nutrition in mind so they could try analysis of methylation themselves. The development and application of the tool has been published and the CandiMeth software is available publicly in the GitHub repository at https://github.com/sjthursby/CandiMeth.
Highlights in regards to capacity building are the outstanding achievements of Dr Aoife Caffrey, Postdoctoral Researcher from UU. Dr Aoife Caffrey received the DSM Bright Science Award for Innovative PhD Research (€6,000) for her studies on "Maternal folate nutrition and offspring brain health", presented at the 13th Federation of European Nutrition Societies (FENS) conference, October 2019, in Dublin, Ireland. Dr Aoife Caffrey also received the University of Ulster Best PhD Thesis Award in 2020 (£250). For her virtual poster presentation at the FASEB Summer Research Conference on Folic Acid, Vitamin B12, and One-Carbon in August 2020, Dr Caffrey won the competitive FASEB Postdoctoral Poster Presentation Award (US $400). Congratulations, Aoife!
We are further pleased to report that Dr Sara-Jayne Thursby from UU has accepted a prestigious postdoc position at the Johns Hopkins Medical School in the US. Further, Dr Rachelle Irwin secured a Lecturer position in her field at UU, where she remains actively involved in her research program and has taken on core teaching roles.
4.1 List of publications
|Authors||Title||Year, Issue, PP||Partners Number||Doi|
|Cavallé-Busquets P, Inglès-Puig M, Fernandez-Ballart JD*, Haro-Barceló J, Rojas-Gómez A*, Ramos-Rodriguez C, Ballesteros M, Meyer K, Ueland PM, Murphy MM* (*JPI HDHL Project Partner/Student)||Moderately elevated first trimester fasting plasma total homocysteine is associated with increased probability of miscarriage||https://doi.org/10.1016/j.biochi.2020.01.008|
|Thursby SJ, Lobo DK, Pentieva K*, Zhang SD, Irwin RE*, Walsh CP* (*JPI HDHL Project Partner)||CandiMeth: Powerful yet simple visualisation and quantification of DNA methylation at candidate genes||Doi: 10.1093/gigascience/giaa066|
|Matusheski N, Caffrey A*, Christensen L, Mezgec S, Surendran S, Hjorth MF, McNulty H*, Pentieva K*, Roager HM, Seljak BK, Vimaleswaran KS, Remmers M, Peter S (*JPI Project Partners)||Diets, nutrients, genes and the microbiome: Recent advances in personalised nutrition||https://doi.org/10.1017/S0007114521000374|
|Roigé-Castellví J, Murphy M*, Voltas N, Solé-Navais P, Cavallé-Busquets P, Fernàndez-Ballart J*, Ballesteros M, Canals J* (*JPI Project Partners)||A prospective study of maternal exposure to smoking during pregnancy and behavioural development in the child||http://dx.doi.org/10.1007/s10826-021-01978-4|
|Ondicova M*, Irwin RE*, Thursby SJ*, Hilman L, Caffrey A*, Cassidy T, McLaughlin M, Lees-Murdock DJ, Ward M*, Murphy M*, Lamers Y*, Pentieva K*, McNulty H*, Walsh CP* (*JPI Project Partners)||Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms||https://doi.org/10.1186/s13148-022-01282-y|
|McNulty H*, Rollins M, Cassidy T, Caffrey A*, Marshall B, Dornan J, McLaughlin M, McNulty BA, Ward M*, Strain JJ, Molloy AM, Lees-Murdock DJ, Walsh CP*, Pentieva K* (*JPI Project Partners)||Effect of continued folic acid supplementation beyond the first trimester of pregnancy on cognitive performance in the child: a follow-up study from a randomized controlled trial (FASSTT Offspring Trial)||https://doi.org/10.1186/s12916-019-1432-4|
|Caffrey A*, Pentieva K*, McNulty H*, Gaur P, Talcott JB, Witton C, Cassidy T, McLaughlin M, Lees-Murdock DJ, Irwin RE*, Walsh CP*, Prasad G (*JPI HDHL Project Partner)||Effect of folic acid supplementation during pregnancy on brain health of the child at 11 years: the FASSTT Offspring trial||https://doi.org/10.1017/S0029665120004553|
|Caffrey A*, McNulty H*, Rollins M, Prasad G, Gaur P, Talcott JB, Witton C, Cassidy T, Marshall B, Dornan J, Moore A, Ward M*, Strain JJ, Molloy A, McLaughlin M, Lees-Murdock DJ, Walsh CP*, Pentieva K*||Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial||https:doi.org/10.1186/s12916-021-01914-9|
|Rojas-Gómez A*, Solé-Navais P, Cavallé-Busquets P, Ornosa-Martin G, Grifoll C, Ramos-Rodriguez C, Fernandez-Ballart J*, Masana L, Ballesteros M, Ueland PM, Murphy MM*||Pregnancy homocysteine and cobalamin status predict childhood metabolic health in the offspring||https://doi.org/10.1038/s41390-022-02117-5|
4.2 Presentation of the project
|Target group||Authors||Means of communication||Hyperlink|
|Scientific - March 2019||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||Oral presentation|
|Scientific - June 2019||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||Poster presentation|
|Scientific - June 2019||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||Oral presentation|
|Scientific - June 2019||Assoc. 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||Oral presentation|
|Scientific - June 2019||Dr Aoife Caffrey, "Effect of folic acid supplementation during pregnancy on cognitive performance of the child at 11 years: the FASSTT Offspring trial", 12th International Conference on One Carbon Metabolism, B-Vitamins and Homocysteine, Spain, 9th-13th June 2019||Poster presentation|
|Scientific - June 2019||Prof Colum Walsh, “EpiFASSTT- Epigenetic effects on children’s psychosocial development in a randomised trial of Folic Acid Supplementation in Second and Third trimester”, Seminar at the Human Nutrition Research Centre, Newcastle University, UK||Oral presentation|
|Scientific - August 2019||Miroslava Ondicova, “A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57”, International symposium Epigenetic Inheritance: Impact for Biology and Society, ETH Zurich, Switzerland||Poster presentation|
|Scientific - October 2019||Prof Kristina Pentieva, "Maternal folic acid supplementation and offspring health: are there benefits beyond NTD?", 13th European Nutrition Conference, Ireland, 15th-18th October 2019||Oral presentation|
|Scientific - October 2019||Dr Aoife Caffrey, "Maternal folate nutrition and offspring brain health", 13th European Nutrition Conference, Ireland, 15th-18th October 2019||Oral presentation|
|Scientific - October 2019||Dr Aoife Caffrey, “Effect of folic acid supplementation during pregnancy on brain health of the child at 11 years: the FASSTT Offspring trial”, 13th European Nutrition Conference, Ireland, 15th-18th October||Poster presentation|
|Professional Practitioners, Public/other audiences, Industry/Business, Supporters, Undergraduate students, Postgraduate students, Study participants or study members, Patients, carers and/or patient groups, Third sector organisations - ongoing||EpiBrain Project twitter account: @EpiBrain_JPI||Twitter website|
|Scientific - August 2020||Dr Aoife Caffrey, "Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: An 11-year follow-up from a randomized clinical trial", FASEB Summer Research Conference on Folic Acid, Vitamin B12 and One-Carbon Metabolism (virtual)||Poster presentation|
|Scientific - August 2020||Prof. Michelle Murphy, "Preconception and first trimester folic acid supplement use and folate status. The Reus Tarragona Birth Cohort", FASEB Summer Research Conference on Folic Acid, Vitamin B12, and One-Carbon Metabolism (virtual)||Poster presentation|
|Professional Practitioners, Public/other audiences, Industry/Business, Supporters, Undergraduate students, Postgraduate students, Study participants or study members, Patients, carers and/or patient groups, Third sector organisations - ongoing||EpiBrain website: https://www.epibrain-folate.com||Website|
|Scientific - April 2022||Helene McNulty*, Invited lecture at the 10th International Nutrition and Dietetics Congress. “From fetal life to the ageing brain: Effect of folate and related B vitamins’’ Istanbul, Turkey (as E-Congress), 2022.04.18||Oral presentation|
|Scientific - September 2022||Ondičová M, Irwin RE*, Thursby SJ, Hilman L*, Caffrey A*, Cassidy T, McLaughlin M, Lees Murdock DJ, Ward M*, Murphy M*, Lamers Y*, Pentieva K*, McNulty H*, Walsh CP*, Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms, 26th Meeting of the Irish Society of Human Genetics, Dublin, Ireland, 16.09.22||Oral presentation|
|Scientific - September 2022||Luke Hilman*, Poster Presentation and abstract publication, 26th Meeting of the Irish Society of Human Genetics Conference, Dublin, Ireland, 16.09.22||Poster presentation|
|Scientific - November 2022||Amy Tan, PhD student, "Prenatal folic acid and related B-vitamins and cognitive development – a transnational approach to study early programming of brain function", Canadian Institutes of Health Research (CIHR) Institute of Nutrition, Metabolism and Diabetes (INMD) Advisory Board Poster Session/Meet & Greet, 2022||Poster presentation|
4.3 List of submitted patents and other outputs
|Patent licence||Partners involved||Year||International eu or national patent||Comment|
|CandiMeth software||UU||2019-2020||available publicly in the GitHub repository at https://github.com/sjthursby/CandiMeth|