Harnessing DNA methylation variation between populations to understand disease discordance across ancestries

Lead Research Organisation: University of Bristol
Department Name: Bristol Medical School

Abstract

DNA methylation (DNAm) is an epigenetic mechanism that plays a central role in gene regulation. It helps to define how cells respond to genetic and environmental signals and, ultimately, contributes to whole system health and disease status.

Levels of DNAm differ from one person to another. However, it is unclear how much of the variation in DNAm levels is caused by genetic or environmental factors and if such effects also relate to human phenotypes. Understanding the relationships between DNAm, genetics and environment is essential for both understanding pathways of health and disease and disease consequences.

Prior research has been limited to populations of European ancestry, restricting understanding of DNAm variation to limited contexts. This is a crucial knowledge gap because there are known genetic and environmental differences in drug response and disease risk factors across population groups worldwide which may be attributable to DNAm variation.

Evaluating DNAm variation in diverse population groups allows comparison across varying genetic and environmental exposure profiles. Identification of disease pathways common to all populations will represent mechanisms of health and disease that are common across all humans. This allows identification of drug targets that will be effective in any population group.

Identification of disease pathways restricted to specific genetic and/or environmental exposure profile will reflect adaptation to environmental and genetic context. This will allow identification of molecular mechanisms that underpin the disease discordance that we observe across global populations and highlight opportunities for targeted treatments.

Our first project aim is to map genetic and environmental determinants of human DNAm variation to understand mechanisms of DNAm variability. We will generate a catalog of genetic associations with DNAm across populations worldwide. This catalog will be used to assess which of the identified genetic associations with DNAm are also associated with human complex traits. This is important because the findings can inform the functional role of phenotype-associated genetic variation, and ultimately - our understanding of the mechanisms underlying human phenotype variation.

The second aim of the project is to understand mechanisms of disease and disease discordance observed between population groups for childhood and cardiometabolic disease related phenotypes.

This project focusses on childhood and cardiometabolic disease for which there is substantial disease discordance and health disparity across populations. For example, diabetes risk is substantially higher in individuals of South Asian origin even after accounting for known genetic and environmental risk factors. Identification of DNAm variation associated with type 2 diabetes that is context specific will contribute to explaining excess type 2 diabetes risk in the South Asian population group. In doing so, Identification of disease pathways restricted to specific genetic and/or environmental exposure profiles brings the opportunity to target treatment or intervention where it is effective.

This research builds a global partnership of teams to bring together genetic and epigenetic data collected from individuals worldwide. A key aspect of this proposal is building equitable partnerships between these teams. This is essential in order to build capacity for research in genetically diverse datasets and to provide internationally relevant research on cardiometabolic and child health phenotypes
Identification of common and context specific mechanisms of health and disease mediated by DNAm is of high health impact because it will enable actions to reduce global health disparity and inequity via targeted interventions or treatments.

Technical Summary

DNA methylation (DNAm) variation plays a key role in gene regulation, helps cells to respond to environmental signals and ultimately contributes to whole system health and disease status. Inter-individual DNAm variation is influenced by both genetic and environmental factors. Understanding the relationships between DNAm, genetics and environment is essential for both understanding pathways of health and disease and disease consequences.

In aim 1, we address a key knowledge gap by using diverse global datasets to identify genetic and environmental determinants of DNAm variation in diverse environmental and genetic contexts. Prior research is heavily biased towards relatively homogeneous European populations. A key output is an open source mQTL resource which will be used to identify functional pathways of multi-ancestry GWAS and EWAS within the project and is likely to be a resource of international interest.

In aim 2, we delineate mechanisms of disease and disease discordance observed between population groups for childhood and cardiovascular related phenotypes using multi-ancestry EWAS. Identification of disease pathways common to all populations will represent essential mechanisms of health and disease, uncovering potentially generalizable drug targets. Identification of disease pathways restricted to specific genetic and/or environmental exposures will reflect adaptation to environmental and genetic context. This will enable discovery of novel disease aetiology and molecular mechanisms underpinning disease discordance observed across global populations. It will also potentially predict differences in response to treatment or intervention between population groups. This aim also tackles generalizability of DNAm predictors to improve exposure and risk prediction which is only possible using diverse data.

A further key objective is to form equitable collaborator partnerships, enabling further research initiatives that additionally impact health outcomes.

Publications

10 25 50
 
Description Directing Bristol Medical School Molecular Epidemiology Short Course
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Participants gained knowledge and skills which they were able to apply in their research practice. Example feedback received from anonymous partcipant: "The course helped me to interpret the literature on molecular epidemiology topics, and has better equipped me to engage with more molecular epi researchers which will encourage future research collaborations"
 
Description Directing Bristol Medical School genetic epidemiology short course
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Participants gained knowledge and skills which they used in their research practice.
 
Description IEU Diverse Data Group
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
 
Description IEU training
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact IEU members gained skills in coding, building collaborations, analysing datasets.
 
Description Organising IEU molecular epidemiology meetings
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Sharing and updating knowledge with colleagues and sharing good research practice.
 
Description Training MSc Molecular Epidemiology Unit
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Change is defined as education of students enrolled on the course. Evidence to demonstrate the benefit of the unit is students attaining pass/merit/distinction awards for their studies.
 
Description Evaluating the role of DNA methylation changes in very early preterm birth
Amount $443,323 (USD)
Funding ID 1R21HD113774-01A1 
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 01/2025 
End 12/2026
 
Description Leveraging multi-omics approaches to identify and predict subtypes of atopic dermatitis
Amount £95,000 (GBP)
Organisation British Skin Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2025 
End 09/2028
 
Title Architecture of DataSHIELD deployment for DEEP purposes 
Description DataSHIELD is a software package which allows you to do non-disclosive federated analysis on sensitive data. This description of a reference deployment of DataSHIELD assumes that the intention is to permit disclosure protected data analysis from external organizations, and to have the risk of disclosure mitigated by the use of DataSHIELD. In these circumstances disclosure protection analysis means the data analysts can request analytical operations be performed on the data, but the results of such analysis are summary statistics which are not disclosive, and conform to legal, ethical and governance constraints which are being upheld by the organization. To be clear, at no point will the data analyst have direct access to the data, or a copy of the data, as the sensitive data will not leave the site which is the custodian of the data. 
Type Of Material Improvements to research infrastructure 
Year Produced 2024 
Provided To Others? No  
Impact After deployment of DataSHIELD, each project partner will store their datasets (methylation and covariates) at their local servers and are managed with Opal through the resourcer package. DataSHIELD allows different types of analyses: pooled and meta-analyses. We would like to conduct analyses across different datasets and obtain results as if the data were located in a single computer. 
 
Title github pipeline for EWAS analysis 
Description Epigenome wide association study (EWAS) pipeline has been developed and tested on several in house datasets and one disease phenotype. 
Type Of Material Improvements to research infrastructure 
Year Produced 2023 
Provided To Others? Yes  
Impact Reproducible EWAS findings using different statistical methods 
URL https://github.com/thomasbattram/ad-cse
 
Title github pipeline for mQTL analyses 
Description Josine Min is leading the Genetics of DNA methylation developers group and developed a pipeline to conduct mQTL and EWAS analyses in Europeans. This pipeline has been run by >40 cohorts. This pipeline will be transferred and adopted for DEEP purposes eg for mQTL analyses for non European participants. 
Type Of Material Improvements to research infrastructure 
Year Produced 2024 
Provided To Others? Yes  
Impact This will lead to the largest GWAS of DNA methylation. 
URL https://github.com/genetics-of-dna-methylation-consortium/godmc_phase2/wiki
 
Title Prospective Urban and Rural Epidemiological Study (SA study site) 
Description genotyping and DNA methylation profiling with arrays on 524 samples from PURE (QC finalised and profiled in March 2025) 
Type Of Material Database/Collection of data 
Year Produced 2025 
Provided To Others? No  
Impact Future contribution to DEEP deliverables 
 
Title STEM-GDM cohort (Peru study site) 
Description DNA methylation profiling using Illumina EPIC arrays on 524 samples from the STEM-GDM cohort (QC finalised, profiling in progress) 
Type Of Material Database/Collection of data 
Year Produced 2025 
Provided To Others? No  
Impact Future contribution to DEEP deliverables 
 
Description Partnership with Charles Agyemang 
Organisation Amsterdam Medical Center
Country Netherlands 
Sector Hospitals 
PI Contribution Guidance on sample selection for study analysis.
Collaborator Contribution Staff time, DNA samples from cohort, expertise on DEEP project objectives
Impact We have signed a collaboration agreement between our institutions, relating to work within the DEEP study grant. We have submitted a RODAM research proposal. We have selected individuals whos DNA will be analysed within the project (Genotyping to be completed within next 6 months)
Start Year 2023
 
Description Partnership with Diana Juvinao Quintero/Bizu Gelaye 
Organisation Harvard University
Department Harvard T.H. Chan School of Public Health
Country United States 
Sector Academic/University 
PI Contribution Guidance on sample selection for study analysis.
Collaborator Contribution Staff time, DNA samples from cohort, expertise on DEEP project objectives
Impact We have signed a collaboration agreement between our institutions, relating to work within the DEEP study grant. We have selected individuals whos DNA will be analysed within the project (DNA methylation profiling to be completed within next 6 months)
Start Year 2024
 
Description Partnership with Marlien Pieters 
Organisation North-West University
Country South Africa 
Sector Academic/University 
PI Contribution Guidance on sample selection for genotype and methylation profiling
Collaborator Contribution Staff time, DNA samples from cohort, expertise on DEEP project objectives
Impact We have signed a collaboration agreement between our institutions, relating to work within the DEEP study grant. 524 DNA samples have been sent from North West University to CPGR. These samples have been QCed for genetic and DNAmethylation profiling resulting in good quality DNA.
Start Year 2023
 
Description Partnership with Pradiptajati Kusuma 
Organisation Mochtar Riady Institute for Nanotechnology
Country Indonesia 
Sector Charity/Non Profit 
PI Contribution setting up collaboration agreement
Collaborator Contribution setting up collaboration agreement
Impact We have signed a collaboration agreement between our institutions, relating to work within the DEEP study grant.
Start Year 2024
 
Description Partnership with Rajesh Dikshit 
Organisation Advanced Centre for Treatment, Research and Education in Cancer
Country India 
Sector Hospitals 
PI Contribution Guidance on sample selection for study analysis. Resources (eg standard operating protocols) for laboratory analysis
Collaborator Contribution Laboratory space, staff time, laboratory consumables, DNA samples from cohorts.
Impact Samples from the ACTREC laboratory have been selected ready for analysis within the DEEP study grant. Indian National Ethics clearance application was submitted in summer 2024 (outcome pending).
Start Year 2023
 
Description partnership with Magatte Ndiaye 
Organisation University Cheikh Anta Diop de Dakar
Country Senegal 
Sector Academic/University 
PI Contribution Setting up collaboration agreement
Collaborator Contribution setting up collaboration agreement
Impact We have signed a collaboration agreement between our institutions, relating to work within the DEEP study grant.
Start Year 2024
 
Title Meffil 
Description Meffil is a Rpackage that provides quality control, normalization and epigenome wide association study analyses. We have implemented a saliva reference panel to provide cell count estimates from DNA methylation profiles from saliva samples. We have updated meffil to be compatible with the latest EPICv2 arrays. 
Type Of Technology Software 
Year Produced 2025 
Impact There is wider use of meffil by the epigenetic community. For example, in the Genetics of DNA methylation consortium this package has been widely used. 
 
Title Meffonym 
Description This Rpackage calculates DNA methylation indices of exposure and phenotype. We updated this packages with smoking scores, age acceleration clocks, and a cytomegalovirus serostatus predictor. 
Type Of Technology Software 
Year Produced 2025 
Impact Epigenetic community have been using this package to predict exposures and outcomes. The impact will be that population based studies with DNA methylation data can predict smoking quantity and CMV serostatus which will be more accurate than self-reported variables. 
 
Description In person coordinating team meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact In December 2024, we held a one-day in-person Executive Project Management Team meeting with the coordinating team (principal investigators and co-investigators) in attendance at the London School of Hygiene and Tropical Medicine, London UK.
Year(s) Of Engagement Activity 2024
 
Description Launch meeting for project partners 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Launch meeting with project partners to present aims and deliverables of project
Year(s) Of Engagement Activity 2024
 
Description Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact In January 2024, the DEEP study made a study press release of which further press releases followed:

University of Bristol: ttps://www.bristol.ac.uk/news/2023/october/deep-study.html

South Africa Today: https://southafricatoday.net/lifestyle/health/groundbreaking-genomics-project-will-improve-global-diversity-in-population-health-insight/

MRC Unit The Gambia: https://www.lshtm.ac.uk/research/units/mrc-gambia/news/394956/groundbreaking-genomics-project-will-improve-global-diversity-population

MRC/UVRI and LSHTM Uganda Research Unit: https://www.lshtm.ac.uk/research/units/mrc-uganda/news/395276/groundbreaking-genomics-project-improve-global-diversity-population-health

The Hindu: https://www.thehindu.com/news/national/telangana/csir-ccmb-study-to-understand-genetics-behind-diseases/article67412977.ece#:~:text=The%20project%20%E2%80%94%20%E2%80%9CDiverse%20Epigenetic%20Epidemiology,and%20North%20and%20South%20America.
Year(s) Of Engagement Activity 2024
URL https://www.bristol.ac.uk/news/2023/october/deep-study.html
 
Description Project website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Set up project website to engage general public and other academics
Year(s) Of Engagement Activity 2024
URL https://www.deep-epigenetics.org/