Early-life Nutritional Programming of Metabolic Health through Epigenetic Pathways

ERA-HDHL JFA2 “Nutrition & the Epigenome” (Epigenome)
Early-life Nutritional Programming of Metabolic Health through Epigenetic Pathways
Janine Felix
Erasmus MC, University Medical Center Rotterdam
The Netherlands


Partner Organization Partner Country
University of BristolUnited Kingdom
Wageningen UniversityThe Netherlands
University of British ColumbiaCanada
Ludwig-Maximilians-Universität MünchenGermany
Barcelona Institute for Global Health (ISGlobal)Spain

1. Overall project description

1.1 Summary

Pregnancy and infancy are critical periods for nutritional programming of metabolic health. Epigenetic changes such as DNA methylation seem to have a crucial role linking early-life nutrition to metabolic health across the life course. The aim of NutriPROGRAM is to identify early-life nutrition-related factors and related epigenetic pathways leading to metabolic adaptations and disease across the life course. The objectives are to:

1) Harmonize and define the nutrition-related and metabolic factors and create new, integrated nutrition-related factors;

2) Identify differential DNA methylation related to maternal and infant nutrition-related factors and to susequent risk factors for metabolic health and disease across the life course;

3) Identify effects of preconception/early-pregnancy and infancy nutritional interventions on childhood DNA methylation and associations with metabolic health;

4) Study cause-and-effect relationships of DNa methylation in the associations of early-life nutrition-related factors and later metabolic health;

5) Characterize molecular mechanisms through which nutrition-related DNA methylation changes lead to developmental adaptations.

In the first 11 months of the project, NutriPROGRAM partners have established an inventory of available maternal and infant nutrition-related factors, which is now being used as a basis for harmonized analyses. Current work focuses on pregnancy vitamin B12 levels, glycemic index and load, and Mediterranean diet in related to DNA methylation. So far, NutriPROGRAM partners have found that DNA methylation levels at over 900 sites in cord blood are related to birth weight. In a further study, we did not find associations of newborn and childhood DNA methylation with liver fat fraction at school age. Work is ongoing on multiple epigenome-wide analyses examining associations of maternal and infant dietary exposures and childhood DNA methylation, as well as on associations of DNA methylation with childhood and adolescence cardiometabolic outcomes.

We expect that NutriPROGRAM will:

1) Create a set of harmonised and integrated nutrition-related factors that can be used by scientists studying the relationships between nutrition and health;

2) Lead to a better understanding of the role of DNA methylation in the pathways underlying the relation of early-life nutrition and metabolic health;

3) Lead to a better understanding of causality and modification of DNA methylation in these pathways. This will be a starting point for prevention of obesity, blood lipid disorders and type 2 diabetes;

4) Contribute to the development of methods to help identify the most promising findings from DNA methylation studies for further research;

5) Form a sustainable, international network of researchers on early-life nutrition, epigenetics and long-term metabolic outcomes that will lay the foundation for further research in this area for many years to come.



1.2 Highlights

Much of the core work in NutriPROGRAM is still ongoing. We describe here two finalized projects.

Project 1: Associations of DNA methylation with birth weight

Birthweight is associated with health outcomes across the life course. DNA methylation may be an underlying mechanism. In a large meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts, including three NutriPROGRAM partners, in collaboration with the Pregnancy And Childhood Epigenetics Consortium, we found that DNA methylation in neonatal blood is associated with birthweight at 914 sites. The difference in birthweight ranged from -183 to 178 grams per 10% increase in methylation. Birthweight-related DNA methylation sites partly overlapped with some DNA methylation sites that were previously reported to be related to maternal smoking and to maternal body mass index in pregnancy, but not with those related to folate levels in pregnancy. Whether these associations are causal or explained by other factors influencing DNA methylation requires further research.

Project 2: Newborn and childhood differential DNA methylation and liver fat in school-age children.

Non-alcoholic fatty liver disease is the most common chronic liver disease in children in western countries. Adverse early-life exposures are associated with higher liver fat percentages in children. Differential DNA methylation may underlie these associations. We aimed to identify differential DNA methylation in newborns and children associated with liver fat accumulation in childhood. We also examined whether DNA methylation at 22 cytosine-phosphate-guanine sites (CpGs) associated with adult non-alcoholic fatty liver disease is associated with liver fat in children. Within the population-based prospective Generation R Study, we analyzed epigenome-wide DNA methylation data of 785 newborns and 344 10-year-old children in relation to liver fat fraction at 10 years, measured by Magnetic Resonance Imaging. No single CpGs and no differentially methylated regions were associated with liver fat accumulation. None of the 22 known adult CpGs were associated with liver fat in children. We conclude that DNA methylation at birth and in childhood was not associated with liver fat accumulation in 10-year-old children in this study. This may be due to modest sample sizes or DNA methylation changes being a consequence rather than a determinant of liver fat.

4. Impact

4.1 List of publications

AuthorsTitleYear, Issue, PPDoiPdf
Sharp GC*, Schellhas L, Richardson SS, Lawlor DATime to cut the cord: recognizing and addressing the imbalance of DOHaD research towards the study of maternal pregnancy exposures10.1017/S2040174419000072
Neumann A, Walton E, Alemany S, Cecil C, González JR, Demissie Jima D, Lahti J, Tuominen ST, Barker ED, Binder E, Caramaschi D, Carracedo A, Czamara D, Evandt J, Felix JF*, Fuemmeler BF, Gutzkow KB, Hoyo C, Julvez J, Kajantie E, Laivuori H, Maguire R, Maitre L, Murphy SK, Murcia M, Villa PM, Sharp GC*, Sunyer J, Raikkönen K, Bakermans-Kranenburg M, Van IJzendoorn M, Guxens M, Relton CL, Tiemeier HAssociation between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis10.1101/806844
Küpers LK*, Monnereau C, Sharp GC*, Yousefi P, Salas LA, Ghantous A, Page CM, Reese SE, Wilcox AJ, Czamara D, Starling AP, Novoloaca A, Lent S, Roy R, Hoyo C, Breton CV, Allard C, Just AC, Bakulski KM, Holloway JW, Everson TM, Xu CJ, Huang RC, van der Plaat DA, Wielscher M, Merid SK, Ullemar V, Rezwan FI, Lahti J, van Dongen J, Langie SAS, Richardson TG, Magnus MC, Nohr EA, Xu Z, Duijts L, Zhao S, Zhang W, Plusquin M, DeMeo DL, Solomon O, Heimovaara JH, Jima DD, Gao L, Bustamante M*, Perron P, Wright RO, Hertz-Picciotto I, Zhang H, Karagas MR, Gehring U, Marsit CJ, Beilin LJ, Vonk JM, Jarvelin MR, Bergström A, Örtqvist AK, Ewart S, Villa PM, Moore SE, Willemsen G, Standaert ARL, Håberg SE, Sørensen TIA, Taylor JA, Räikkönen K, Yang IV, Kechris K, Nawrot TS, Silver MJ, Gong YY, Richiardi L, Kogevinas M, Litonjua AA, Eskenazi B, Huen K, Mbarek H, Maguire RL, Dwyer T, Vrijheid M, Bouchard L, Baccarelli AA, Croen LA, Karmaus W, Anderson D, de Vries M, Sebert S, Kere J, Karlsson R, Arshad SH, Hämäläinen E, Routledge MN, Boomsma DI, Feinberg AP, Newschaffer CJ, Govarts E, Moisse M, Fallin MD, Melén E, Prentice AM, Kajantie E, Almqvist C, Oken E, Dabelea D, Boezen HM, Melton PE, Wright RJ, Koppelman GH, Trevisi L, Hivert MF, Sunyer J, Munthe-Kaas MC, Murphy SK, Corpeleijn E, Wiemels J, Holland N, Herceg Z, Binder EB, Davey Smith G, Jaddoe VWV, Lie RT, Nystad W, London SJ, Lawlor DA, Relton CL, Snieder H, Felix JF*Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight10.1038/s41467-019-09671-3
Gervin K, Salas LA, Bakulski KM, van Zelm MC, Koestler DC, Wiencke JK, Duijts L, Moll HA, Kelsey KT, Kobor MS*, Lyle R, Christensen BC, Felix JF*, Jones MJSystematic Evaluation and Validation of Reference and Library Selection Methods for Deconvolution of Cord Blood DNA Methylation Data10.1186/s13148-019-0717-y
Marchioro L, Geraghty AA, Uhl O, Shokry E, O’Brien EC, Koletzko B*, McAuliffe FMEffect of a low glycaemic index diet during pregnancy on maternal and cord blood metabolomic profiles: results from the ROLO randomized controlled trial10.1186/s12986-019-0378-z
Geurtsen ML, Jaddoe VWV, Salas LA, Santos S, Felix JF*Newborn and childhood differential DNA methylation and liver fat in school-age children10.1186/s13148-019-0799-6
Caramaschi D, Hatcher C, Mulder RH, Felix JF*, Cecil CAM, Relton CL, Walton EEpigenome-wide association study of seizures in childhood and adolescence10.1186/s13148-019-0793-z
Sikdar S, Joehanes R, Joubert BR, Xu CJ, Vives-Usano M, Rezwan FI, Felix JF*, Ward JM, Guan W, Richmond RC, Brody JA, Küpers LK*, Baïz N, Håberg SE, Smith JA, Reese SE, Aslibekyan S, Hoyo C, Dhingra R, Markunas CA, Xu T, Reynolds LM, Just AC, Mandaviya PR, Ghantous A, Bennett BD, Wang T, The BIOS Consortium, Bakulski KM, Melen E, Zhao S, Jin J, Herceg Z, Meurs JV, Taylor JA, Baccarelli AA, Murphy SK, Liu Y, Munthe-Kaas MC, Deary IJ, Nystad W, Waldenberger M, Annesi-Maesano I, Conneely K, Jaddoe VW, Arnett D, Snieder H, Kardia SL, Relton CL, Ong KK, Ewart S, Moreno-Macias H, Romieu I, Sotoodehnia N, Fornage M, Motsinger-Reif A, Koppelman GH, Bustamante M,* Levy D, London SJComparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking10.2217/epi-2019-0066
Rudloff S, Bührer C, Jochum F, Kauth T, Kersting M, Körner A, Koletzko B*, Mihatsch W, Prell C, Reinehr T, Zimmer KPVegetarian diets in childhood and adolescence: Position paper of the nutrition committee, German Society for Paediatric and Adolescent Medicine (DGKJ)10.1186/s40348-019-0091-z
Reinehr T, Schnabel D, Wabitsch M, Bechtold-Dalla Pozza S, Bührer C, Heidtmann B, Jochum F, Kauth T, Körner A, Mihatsch W, Prell C, Rudloff S, Tittel B, Woelfle J, Zimmer KP, Koletzko B*Vitamin D supplementation after the second year of life: joint position of the Committee on Nutrition, German Society for Pediatric and Adolescent Medicine (DGKJ e.V.), and the German Society for Pediatric Endocrinology and Diabetology (DGKED e.V.)10.1186/s40348-019-0090-0
Koletzko B*, Bührer C, Ensenauer R, Jochum F, Kalhoff H, Lawrenz B, Körner A, Mihatsch W, Rudloff S, Zimmer KPComplementary foods in baby food pouches: position statement from the Nutrition Commission of the German Society for Pediatrics and Adolescent Medicine (DGKJ, e.V.)10.1186/s40348-019-0089-6

4.2 Presentation of the project

Target groupAuthorsMeans of communicationHyperlinkPdf
Scientific communityGemma Sharp. Poster entitled “Exploring Prenatal Influences on Childhood Health: What Role for Mums and Dads”. Developmental origins of health and disease (DOHaD) conference, Melbourne, Australia, October 21st 2019Poster
Scientific communityGemma Sharp. Poster entitled “Using epigenetic and genetic approaches to identify factors that influence paternal participation in birth cohort studies”. Developmental origins of health and disease (DOHaD) conference, Melbourne, Australia, October 21st 2019Poster
Scientific communityGemma Sharp. Poster entitled “It’s the Mother!: Recognising and addressing the imbalance in DOHaD research towards the study of maternal pregnancy exposures”. Developmental origins of health and disease (DOHaD) conference, Melbourne, Australia, October 21st 2019Poster
General publicMichael Kobor. Several articles were published in the general media in October 2019 about our paper “The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells”. e.g.: 1. “New DNA 'clock' could help measure development in young children” - Science Daily, 2. “A DNA "Clock" To Measure Development in Young Children” - Technology Networks, 3. “First "molecular clock" for kids could reveal early signs of autism” - New Atlas, 4. “Researchers Identify DNA Methylation Signature Linked to Aging, Autism in Children” - Genome WebNewspaper articles
General publicMichael Kobor. Policy Horizons Canada, “Social Epigenetics: How Your Early Life Environment Gets “Under Your Skin”, November 14, 2019. National blog post

4.3 List of submitted patents and other outputs

Patent licencePartners involvedYearInternational eu or national patentCommentPdf


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