1. DNA methylation is a product of both genetics and the environment, and is associated with disease.
2. DNA methylation marks have several potential uses, including as prognostic markers that incorporate genetic and environmental risk, as markers of intervention efficacy, and as surrogate endpoints for drug discovery.
3. Studies utilizing disease-associated DNA methylation marks can provide insights into DNA methylation's role in disease etiology and its potential as a biomarker for precision medicine approaches.
Biomedical Informatics 706: Precision Medicine with exposures
precision_medicine_080916_nonconfidential
1. Correcting the epigenetic
consequence of personal genetic
and environmental risk
Joanna D Holbrook
Professor of Bioinformatics, NIHR Southampton Biomedical Research
Centre, University of Southampton and University Hospital Southampton
NHS Foundation Trust and Senior Principal Investigator, Singapore
Institute for Clinical Sciences (SICS)
The 3rd Precision Medicine Congress
13th September 2016
2. Our genetics and our environment
define our disease risk
Genetics
Environment
Disease
time
3. The molecular state of malignancy
can guide cancer treatment
Genetics
Environment
Disease
time
Tumour
Protein
RNA
Genetics
4. Stratified medicine for non-
malignant disorders
Genetics
Environment
Disease
time
Peripheral tissue
Protein
RNA
5. DNA methylation is a product of
genetics and environment and is
associated with disease
Genetics
Environment
Disease
time
DNA
methylation
6. Uses for disease-associated DNA
methylation marks
1. As prognostic markers which combine
consequences of genetic and environmental
risk
2. As markers of intervention efficacy.
3. As surrogate endpoints for drug discovery
4. As drug targets – the modifiable aspect of
genetic risk
7. Three statements that need to
be evidenced
1. DNA methylation is a product of both
genetics and environment
2. DNA methylation is associated with disease
3. There is evidence that its causative for some
combinations of loci and disease. (However,
for most combinations, reverse causation or
confounding has not been excluded)
8. Three statements that need to
be evidenced
1. DNA methylation is a product of both
genetics and environment
2. DNA methylation is associated with disease
3. There is evidence that its causative for some
combinations of loci and disease. (However,
for most combinations, reverse causation or
confounding has not been excluded)
9. 9
DNA polymorphism can specify inter-
individual variation in DNA methylation
Individual environment can affect DNA
methylation patterns
10. Data from the GUSTO birth cohort
Preconceptional
health
Anxiety – depression
Nutritional status
etc..
Gestational
environment
Cortisol
Hyperglycemia
Hypertension
etc..
Birth and infancy
conditions
Delivery mode
Mode of feeding
etc..
Birth outcomes
Gestational age
Birth weight/adiposity
Brain size and connectivity Development
Metabolism
Neurocognition
Disease
Obesity
pathopsychology
How does my body remember
what happened to me
previously, and how does
that affect subsequent
health?
13. Methylation at majority of VMRs
best explained by interaction of
genetics and environment
G x E
(74.6%)
Genotype
alone
(25.4%)
Competing models
Genotype model:
Meth ~ G1 + gender + cell
Environment model:
Meth ~ Envi + gender + cell
Genotype X Environment model:
Meth ~ G2 + Envi + G2xEnvi + gender + cell
14. There is often a
genotypic class
“sensitive” to
environment
15. Three statements that need to
be evidenced
1. DNA methylation is a product of both
genetics and environment
2. DNA methylation is associated with disease
3. There is evidence that its causative for some
combinations of loci and disease. (However,
for most combinations, reverse causation or
confounding has not been excluded)
18. Three statements that need to
be evidenced
1. DNA methylation is a product of both
genetics and environment
2. DNA methylation is associated with disease
3. There is evidence that its causative for some
combinations of loci and disease. (However,
for most combinations, reverse causation or
confounding has not been excluded)
19. DNA methylation is predictive of
later phenotype
HES1 methylation at birth
Child’sIQat4yearsofage
GxE
GxE
GxE
M P
P M
P
M
20. AHRR and F2RL3 methylation is
causal in the pathway from
smoking to lung cancer
37% of the total effect of
smoking on lung cancer
risk is mediated via
methylation in AHRR and
FR2L3
And its reversible
21. Three statements that need to
be evidenced
1. DNA methylation is a product of both
genetics and environment
2. DNA methylation is associated with disease
3. There is evidence that its causative for some
combinations of loci and disease. (However,
for most combinations, reverse causation or
confounding has not been excluded)
22. Uses for disease-associated DNA
methylation marks
1. As prognostic markers which combine
consequences of genetic and
environmental risk
2. As markers of intervention efficacy.
3. As surrogate endpoints for drug discovery
23. Uses for disease-associated DNA
methylation marks
1. As prognostic markers which combine
consequences of genetic and
environmental risk
2. As markers of intervention efficacy.
3. As surrogate endpoints for drug discovery
24. Epigenetic Biomarkers and
Determinants of
Cardiovascular Risk in Children
Genetics
Preconceptional/
Gestational
Environment
CVD risk factors
at 12yo
time
DNA methylation
At birth
Childhood Environment
Adiposity in
infancy and
childhood
DNA
methylation at
12yo
Karen Lillycrop
Mark Hanson
CVD in
adulthood
?
?
25.
26. Uses for disease-associated DNA
methylation marks
1. As prognostic markers which combine
consequences of genetic and
environmental risk
2. As markers of intervention efficacy
3. As surrogate endpoints for drug discovery
27. Preventing vertical transmission of
diabetes risk
Maternal and
offspring genetics
Pre-conceptional and gestational
environment esp. maternal
hyperglycemia
Offspring
metabolic profile
in adulthood
time
DNA methylation
At birth
Behavioural
(UPBEAT)
Or nutritional
(NIPPER)
intervention
28. Uses for disease-associated DNA
methylation marks
1. As prognostic markers which combine
consequences of genetic and
environmental risk
2. As markers of intervention efficacy
3. As surrogate endpoints for drug discovery
29. In conclusion
• DNA methylation biomarkers are a promising avenue for expanding
preventative medicine to non-malignant and complex diseases.
• DNA methylation is downstream of genetic and environmental influences on
disease,
…. And upstream of disease.
• In some instances, DNA methylation marks have been shown to be on the
causal pathway to disease.
• Disease associated DNA methylation marks have utility as prognostic
biomarkers, biomarkers for intervention efficacy and as surrogate endpoints
for discovery of new therapeutics.
• Studies to pursue these uses will shed further light on the role of DNA
methylation in disease etiology.
30. Acknowledgements
• Epigen:
– The Liggins Institute, NZ
– The University of Auckland, NZ
– Human Development and Health Academic Unit, University of
Southampton, UK
– MRC Lifecourse Epidemiology Unit, University of Southampton, UK
– Singapore Institute for Clinical Sciences (SICS), A*STAR, SG
– The National University of Singapore, SG