The Genetic Epidemiology of Atopic Dermatitis

Lead Research Organisation: University of Bristol
Department Name: Social Medicine

Abstract

Eczema is a common chronic skin disease affecting up to 30% of children and 10% of adults. The condition has a considerable impact on the lives of sufferers and their families and a significant economic burden.

Though we know eczema is influenced by genetic factors, few of the actual genes involved have been identified. This project will use a range of the most up-to-date technologies and analysis methods to identify additional genes involved in susceptibility to eczema.

Eczema can range in its severity, age-of-onset and persistence, with some sufferers also having other related 'allergic' conditions such as asthma and hayfever. Therefore, there are likely to be genes that influence very specific types of eczema and other genes that result in susceptibility to allergic conditions in general.

This project will primarily use data from the Avon Longitudinal Study of Parents and Children (ALSPAC), which recruited pregnant women in the early 1990s and has followed up the children (and parents) with regular questionnaires and clinic visits, as well as collecting DNA samples. I will combine the findings from this study with other studies of eczema genetics from around the world, to confirm our findings.

I will use questionnaire and clinic data in ALSPAC to refine how we assign people as affected eczema cases and controls (and classify the affected individuals as having different types of eczema). I will then (using a number of studies and different methods) compare the genetic information between people with and without eczema (and with different types of eczema), to estimate the extent to which all of the genetic information combined explains susceptibility to AD and identify the specific genes involved. I will also identify which molecular pathways these genes operate in to learn more about how the condition develops. I will test whether it matters whether you inherit these genetic variants from your mother or your father and test whether the effect of genes on whether you develop eczema are influenced by the environment.

The findings from this work will greatly improve our understanding of eczema and will eventually lead to better diagnoses and treatments for those affected.

Technical Summary

A comprehensive program of genetic epidemiological analysis for atopic dermatitis (AD), using state-of-the-art technologies & analytical methods.

Objectives:
1 Refine the AD phenotype definition using latent class analysis in a longitudinal epidemiological study, incorporating various data from multiple time points
2 Quantify the overall contribution made by common genetic variants to AD susceptibility & identify important pathways
3 Carry out a large-scale genome-wide association meta-analysis of improved AD definitions & subtypes
4 Refine existing signals and investigate the role of lower frequency variants in AD using next-generation sequencing
5 Investigate parent-of-origin effects using multi-generational data
6 Investigate 'gene-gene' & 'gene-environment' interactions for AD
7 Functional follow-up of AD associated variants using methylation and expression data.

Main dataset:The Avon Longitudinal Study of Parents And Children. Extensive phenotypic data has been frequently collected via clinics & questionnaires. Mothers & children have imputed genome-wide SNP data & next-generation sequencing (NGS) data will soon be available for the children. Expression and methylation data will also be available.
Additional datasets:Through existing and planned collaborations in the EAGLE consortium, I will have access to a unique resource of datasets, including TwinsUK (with NGS data), the GOYA cohort (with multi-generational data) and two family-based cohorts at QIMR.

Methods:Latent class analysis to investigate the phenotype, whole-genome methods for exploring the common genetic contribution to AD, genome-wide association analysis and meta-analysis to identify associated common variants and interactions, and collapsing techniques for identifying lower frequency variants from NGS data.

This work will increase the molecular understanding of the development of AD. This will in turn enable future treatments for AD to be designed.

Planned Impact

Novel pathways identified as contributing to disease could offer pharmacotherapeutic possibilities.

Beneficiaries:

Patients, clinicians, the NHS:
The increase in knowledge expected through this research is an important early step on the pathway of identifying therapeutic targets and eventually bringing a treatment to market which will impact the health of patients and have an economic impact on the NHS. Increased understanding of the molecular nature of AD will also lead to better diagnosis of the condition, which will also likely benefit the lives of AD patients and have an impact on those involved in the diagnosis and treatment of AD through the NHS.

The study participants and wider community:
By contributing to the breadth of research carried out within ALSPAC, beneficiaries will include the stake-holders of this resource (the participants and the general public). Through press releases and other engagement activities the findings from research carried out within ALSPAC are often disseminated broadly.

Full details of dissemination and engagement activities are in the 'impact to pathways' statement.

Organisations

Publications

10 25 50
 
Description AMS Springboard
Amount £99,977 (GBP)
Funding ID SBF003\1094 
Organisation Academy of Medical Sciences (AMS) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2018 
End 05/2020
 
Description British Skin Foundation Innovative Project Award
Amount £90,000 (GBP)
Organisation British Skin Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Elizabeth Blackwell Institute - Proximity to Discovery Award
Amount £4,683 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2017 
End 08/2017
 
Description Innovative Medicines Initiative 2 Joint Undertaking
Amount € 10,500,000 (EUR)
Funding ID 821511 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 04/2019 
End 03/2024
 
Description Postgraduate extension fellowship
Amount £38,317 (GBP)
Organisation University of Bristol 
Department Elizabeth Blackwell Institute for Health Research
Sector Academic/University
Country United Kingdom
Start 11/2015 
End 08/2016
 
Description EAGLE eczema 
Organisation 23andMe
Country United States 
Sector Private 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Centre for Genomic Regulation (CRG)
Country Spain 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Children's Hospital of Philadelphia
Department Center for Applied Genomics
Country United States 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Erasmus University Rotterdam
Department Generation R Study
Country Netherlands 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Free University of Amsterdam
Country Netherlands 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Harvard University
Country United States 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Helmholtz Association of German Research Centres
Department The Max Delbrück Center for Molecular Medicine (MDC)
Country Germany 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Helmholtz Zentrum München
Department Helmholtz Graduate School Environmental Health (HELENA)
Country Germany 
Sector Public 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Henry Ford Health System (HFHS)
Department Centre for Health Policy
Country United States 
Sector Charity/Non Profit 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Imperial College London
Department School of Public Health
Country United Kingdom 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Karolinska Institute
Department Institute of Environmental Medicine
Country Sweden 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Laboratory for Respiratory and Allergic Diseases
Country Japan 
Sector Public 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Norwegian Institute of Public Health
Department Division of Epidemiology
Country Norway 
Sector Public 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation St George's University of London
Department Population Health Research Institute
Country United Kingdom 
Sector Hospitals 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation Swiss Tropical & Public Health Institute
Department Department of Epidemiology and Public Health (EPH)
Country Switzerland 
Sector Public 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation The Statens Serum Institute (SSI)
Country Denmark 
Sector Public 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation University of Copenhagen
Department Faculty of Health and Medical Sciences
Country Denmark 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation University of Dundee
Department College of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation University of Groningen
Country Netherlands 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation University of Kiel
Country Germany 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation University of Manchester
Department Institute of Inflammation and Repair
Country United Kingdom 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation University of Queensland
Department Genetic Epidemiology Laboratory
Country Australia 
Sector Public 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation University of San Francisco
Department School of Pharmacy and Medicine
Country United States 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description EAGLE eczema 
Organisation University of Western Australia
Department School of Women's and Infants' Health
Country Australia 
Sector Academic/University 
PI Contribution I lead this consortium and lead the analysis team and working group.
Collaborator Contribution Consortium members contribute GWAS results from their individual studies to be meta-analysed by the analysis team. Some members contribute to the analysis team and working group.
Impact Paternoster et al. 2015 Nature Genetics: Atopic dermatitis GWAS paper.
Start Year 2012
 
Description PACE eczema 
Organisation Centre for Genomic Regulation (CRG)
Country Spain 
Sector Academic/University 
PI Contribution I lead the PACE eczema analysis team for meta-analysis epigenome-wide association study
Collaborator Contribution Provide data and analysis ideas/discussion
Impact None yet
Start Year 2015
 
Description PACE eczema 
Organisation Erasmus University Rotterdam
Department Generation R Study
Country Netherlands 
Sector Academic/University 
PI Contribution I lead the PACE eczema analysis team for meta-analysis epigenome-wide association study
Collaborator Contribution Provide data and analysis ideas/discussion
Impact None yet
Start Year 2015
 
Description PACE eczema 
Organisation National Institute of Environmental Health Sciences
Country United States 
Sector Academic/University 
PI Contribution I lead the PACE eczema analysis team for meta-analysis epigenome-wide association study
Collaborator Contribution Provide data and analysis ideas/discussion
Impact None yet
Start Year 2015
 
Description PACE eczema 
Organisation National Institute of Health and Medical Research (INSERM)
Country France 
Sector Public 
PI Contribution I lead the PACE eczema analysis team for meta-analysis epigenome-wide association study
Collaborator Contribution Provide data and analysis ideas/discussion
Impact None yet
Start Year 2015
 
Description PACE eczema 
Organisation Norwegian Mother and Child Cohort (MoBa)
Country Norway 
Sector Public 
PI Contribution I lead the PACE eczema analysis team for meta-analysis epigenome-wide association study
Collaborator Contribution Provide data and analysis ideas/discussion
Impact None yet
Start Year 2015
 
Description PACE eczema 
Organisation University Medical Center Gronigen
Department Rheumatology and Clinical Immunology (UMCG-R)
Country Netherlands 
Sector Hospitals 
PI Contribution I lead the PACE eczema analysis team for meta-analysis epigenome-wide association study
Collaborator Contribution Provide data and analysis ideas/discussion
Impact None yet
Start Year 2015
 
Description PACE eczema 
Organisation University of Southampton
Country United Kingdom 
Sector Academic/University 
PI Contribution I lead the PACE eczema analysis team for meta-analysis epigenome-wide association study
Collaborator Contribution Provide data and analysis ideas/discussion
Impact None yet
Start Year 2015
 
Description article in Exchange magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact I wrote an article called 'Eczema and Genetics' for the National Eczema Society's March 2016 quarterly Exchange magazine. This magazine is sent to ~3,400 members who are mostly either eczema patient's, caregivers or practitioners. The article summarised our recent eczema genetic findings and also answered some more general questions that members of the society often ask about genetics.
Year(s) Of Engagement Activity 2016