Accessible resource for integrated epigenomics studies (ARIES)
Lead Research Organisation:
University of Bristol
Department Name: Faculty of Medicine and Dentistry
Abstract
Epigenetic studies are becoming a central focus of biological research internationally. Epigenetic profiles can serve as exposure markers and as prognostic or predictive biomarkers, with leukocyte methylation currently being the most commonly measured form of epigenetic modification, in the most readily obtainable tissue and one that has undergone epigenetic analysis in many investigations. In regard to this mode of analysis the Avon Longitudinal Study of Parents and their Children (ALSPAC) provides a unique potential resource, in having two-generational data and cord blood and later peripheral blood samples available, allowing for intrauterine influences, intergenerational transmission, change in methylation from birth through to pre-pubertal and post-pubertal age, and investigation of how methylation patterns predict and change with development. Such methylation data would be linked to the extensive exposure, genotype and phenotype data available in ALSPAC. The human data will be coupled with rodent data documenting the relationship between leukocyte and other tissue methylation and gene expression and rodent model tissue banks related to over-nutrition, obesity and ageing. Additional rodent tissues will be banked for future analysis upon request. Data generated will be uploaded for browsing on a custom web-based interface developed specifically for this initiative which will permit the integration of data from multiple sources from both human and rodent sources. The user will have access to data exploration utilities, a graphical genome browser and interactive graphical views of data relationships. The integration of data on epigenetic profiles in this intensively characterised human cohort with rodent epigenetic and transcriptomic data to generate an accessible resource to enhance research in the field of epigenetics for the benefit of the wider scientific community represents a considerable bioinformatic undertaking. We will draw on the expertise of leading scientists in the field of epigenetics and population-based human cohort studies to generate relevant data and combine this with up to date and highly skilled bioinformatics input (developed with substantive previous investment from the BBSRC) to meet our stated objectives. In combination, the proposed generation of biological data together with state of the art bioinformatic tools for data integration and access, would provide an unequivocally world-leading resource for epigenetic studies.
Technical Summary
Serial samples taken at multiple time points across the lifecourse from 1,000 mother-child pairs from ALSPAC will be used to generate genome-wide DNA methylation. The Illumina 450K human methylation array will be used to analyse samples from birth, age 7 and age 15-17 in 1,000 children and samples taken during pregnancy and 17 years later from their mothers. These data will be complemented by methylome sequencing of both the 5-methylcytosine and 5-hyroxymethylcytosine fractions of the genome which will be isolated by immuno-precipitation and sequenced using a next-generation platform. Tandem genome wide methylation and gene expression analysis will be undertaken in mouse tissues (leukocytes, adipose, muscle, liver) using a custom NimbleGen methylation array and Affymetrix gene ST arrays respectively. Further mouse tissues will be harvested and banked for future investigation upon request. The complex primary data generated will be processed and fully integrated using the Ondex system that has been developed under the SABR initiative. In addition to the facility to view these data in an open access browser, users will have the opportunity to access extensive exposure and phenotype information from the ALSPAC cohort using the existing infrastructure. The project will run for 2 years and be managed by a team of academics who have a proven track record in large scale collaborative research and the provision of data and information to the wider scientific community. An international Scientific Advisory Board of leading scientists in epigenetics and bioinformatics will contribute to the oversight of ARIES.
Planned Impact
The ARIES project draws together complementary skills in laboratory, population and bioinformatic aspects of epigenetics to create a unique resource that will be of considerable value to a broad bioscience community spanning both academia and industry, both in the UK and internationally. The population of researchers engaged in the field of epigenetics is growing exponentially and the need for large scale genome-wide locus specific epigenomic data in combination with phenotypic and exposure data has been identified as a research priority by several recent high impact publications. Such information would provide understanding of how the epigenome differs between individuals, how it changes through the life course during the natural ageing process, identify factors that mediate these changes and provide insight into their physiological consequences. The ARIES project will address this knowledge and resource deficit by capitalising on recent advances in genome wide epigenetic methodologies and the availability of samples from a unique parent and child cohort (ALSPAC) which has been extensively phenotypically and genetically characterised over the past 20 years. The inclusion of data from mice to address tissue-specificity of the epigenotype, another major focus of current debate in the field, provides an extra and important dimension. The project will utilise advanced bioinformatic tools to establish a facility to amass, integrate and disseminate multi-dimensional biological information. The incorporation of computational tools and web-based technology is increasingly a feature of scientific research and this project will exemplify the societal impact that such advances can have. As reflected by the letters of support from both academia and industry in the UK, Europe and further afield, the ARIES resource will be utilised widely and accelerate scientific advances in this rapidly emerging field. The proposed timescale of 2 years places ARIES in a highly competitive position, with tangible output well in advance of much larger, more technically demanding global initiatives currently being discussed. Epigenetics has captured the headlines in both the popular and scientific press in recent years partly due to the promise it holds in providing a route through which gene expression can be modulated by pharmacological, dietary, lifestyle or perhaps behavioural interventions. This is particularly important in modern society where in countries such as the UK, the population is ageing and governments are faced with ensuring that the 'health span' of the population increases in parallel with the 'lifespan'. Furthermore, epigenetic mechanisms are clearly important in optimal development, and possible cognitive (and other) deficits of considerable importance in economic and human capital terms may arise through such processes. Any interventions that optimise development and ageing could therefore have a major societal impact. Research in this field is actively being pursued in many domains from basic science laboratories to the pharmaceutical industry. Industrial colleagues have therefore justifiably highlighted the potential that ARIES represents in enhancing the efforts in preventive medicine, the discovery of novel therapeutic targets and the possible application of epigenetic factors as biomarkers of efficacy of interventions and treatments. Modification of the epigenotype is a considerably more tractable target for intervention and prevention strategies than modification of the genotype and therefore has the potential to make a greater impact on public health policies and the wellbeing of the population. Advances in any of these areas would bring considerable economic gain and maintain the UK at the forefront of advances in this area.
Organisations
Publications
Alfano R
(2019)
Socioeconomic position during pregnancy and DNA methylation signatures at three stages across early life: epigenome-wide association studies in the ALSPAC birth cohort.
in International journal of epidemiology
Alfano R
(2023)
Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth.
in BMC medicine
Ambatipudi S
(2018)
Assessing the Role of DNA Methylation-Derived Neutrophil-to-Lymphocyte Ratio in Rheumatoid Arthritis.
in Journal of immunology research
Arathimos R
(2018)
Associations of sex hormone-binding globulin and testosterone with genome-wide DNA methylation.
in BMC genetics
Arathimos R
(2017)
Epigenome-wide association study of asthma and wheeze in childhood and adolescence.
in Clinical epigenetics
Barker ED
(2018)
Inflammation-related epigenetic risk and child and adolescent mental health: A prospective study from pregnancy to middle adolescence.
in Development and psychopathology
Barker ED
(2018)
Annual Research Review: DNA methylation as a mediator in the association between risk exposure and child and adolescent psychopathology.
in Journal of child psychology and psychiatry, and allied disciplines
Battram T
(2019)
Appraising the causal relevance of DNA methylation for risk of lung cancer.
in International journal of epidemiology
Battram T
(2022)
The EWAS Catalog: a database of epigenome-wide association studies
in Wellcome Open Research
Battram T
(2021)
The EWAS Catalog: a database of epigenome-wide association studies
Battram T
(2022)
The EWAS Catalog: a database of epigenome-wide association studies
in Wellcome Open Research
Beckmeyer-Borowko A
(2018)
SERPINA1 methylation and lung function in tobacco-smoke exposed European children and adults: a meta-analysis of ALEC population-based cohorts.
in Respiratory research
Bonilla C
(2021)
Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer.
in Pigment cell & melanoma research
Briollais L
(2021)
DNA methylation mediates the association between breastfeeding and early-life growth trajectories.
in Clinical epigenetics
Caramaschi D
(2020)
Epigenome-wide association study of seizures in childhood and adolescence
in Clinical Epigenetics
Caramaschi D
(2022)
Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills.
in Molecular psychiatry
Caramaschi D
(2021)
Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts.
in Human reproduction (Oxford, England)
Cecil CA
(2016)
Prenatal diet and childhood ADHD: exploring the potential role of IGF2 methylation.
in Epigenomics
Cecil CA
(2016)
DNA methylation and substance-use risk: a prospective, genome-wide study spanning gestation to adolescence.
in Translational psychiatry
Chambers JC
(2015)
Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study.
in The lancet. Diabetes & endocrinology
Cuellar Partida G
(2018)
Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans.
in Human molecular genetics
De Vocht F
(2018)
DNA methylation from birth to late adolescence and development of multiple-risk behaviours.
in Journal of affective disorders
De Vocht F
(2019)
Residential exposure to radon and DNA methylation across the lifecourse: an exploratory study in the ALSPAC birth cohort
in Wellcome Open Research
De Vocht F
(2015)
Assessment of Offspring DNA Methylation across the Lifecourse Associated with Prenatal Maternal Smoking Using Bayesian Mixture Modelling.
in International journal of environmental research and public health
Dunn EC
(2019)
Sensitive Periods for the Effect of Childhood Adversity on DNA Methylation: Results From a Prospective, Longitudinal Study.
in Biological psychiatry
Elliott H
(2013)
Migration and DNA methylation: a comparison of methylation patterns in type 2 diabetes susceptibility genes between indians and europeans
in Journal of Diabetes Research and Clinical Metabolism
Elliott HR
(2017)
Role of DNA Methylation in Type 2 Diabetes Etiology: Using Genotype as a Causal Anchor.
in Diabetes
Elliott HR
(2014)
Differences in smoking associated DNA methylation patterns in South Asians and Europeans.
in Clinical epigenetics
Everson TM
(2019)
Epigenome-wide association study of asthma and wheeze characterizes loci within HK1.
in Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology
Felix JF
(2018)
Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium.
in International journal of epidemiology
Gaunt TR
(2016)
Systematic identification of genetic influences on methylation across the human life course.
in Genome biology
Hillary RF
(2024)
Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts.
in Cell genomics
Holdsworth EA
(2023)
Maternal-infant interaction quality is associated with child NR3C1 CpG site methylation at 7 years of age.
in American journal of human biology : the official journal of the Human Biology Council
Howe LJ
(2019)
Evidence for DNA methylation mediating genetic liability to non-syndromic cleft lip/palate.
in Epigenomics
Joubert BR
(2016)
DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.
in American journal of human genetics
Juvinao-Quintero DL
(2021)
DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts.
in Clinical epigenetics
Kee MZL
(2022)
Fetal sex-specific epigenetic associations with prenatal maternal depressive symptoms.
in iScience
Khouja JN
(2018)
Epigenetic gestational age acceleration: a prospective cohort study investigating associations with familial, sociodemographic and birth characteristics.
in Clinical epigenetics
Kirkbride JB
(2012)
Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects?
in Epigenomics
Küpers LK
(2015)
DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring.
in International journal of epidemiology
Lewis S
(2013)
Approaches for strengthening causal inference regarding prenatal risk factors for childhood behavioural and psychiatric disorders
in Journal of Child Psychology and Psychiatry
Lozano M
(2022)
DNA methylation changes associated with prenatal mercury exposure: A meta-analysis of prospective cohort studies from PACE consortium.
in Environmental research
Luo M
(2021)
Neonatal DNA methylation and childhood low prosocial behavior: An epigenome-wide association meta-analysis.
in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
Description | This research has generated a large scale resource for epigenetic epidemiology research.. It is the first resource of its kind to make large scale DNA methylation data from a population based cohort, generated from serial samples from the same individuals, openly accessible for research use. It has resulted in numerous published outputs involving both methodological developments and epidenome-wide association study findings. ARIES is a major (founding) contributor to several epigenomic consortia. |
Exploitation Route | Data are available via ALSPAC and are widely used by researchers from numerous international institutions. |
Sectors | Environment Healthcare |