Transcript Chris Hammond - Health in Wales

Twin Studies:
common complex disorders
Professor Chris Hammond
St Thomas’ Hospital, London
Dept Twin Research & Genetic Epidemiology
Epigenetics and Twin Studies
• Twin studies
– Unexplained heritability
– Discordant MZ twin model
– Epigenome-wide association studies (EWAS)
• The promise of epigenetics
– New disease mechanisms
– Biomarkers of aging
– Measuring the environment
www.twinsuk.ac.uk
TwinsUK Adult Twin Registry
• Founded 1992 by Tim
Spector
• 11,000 twin volunteers
recruited through media
campaigns
• Representative of healthy
adult population
• ~7,000 with multiple
phenotypes and samples
• Aged 18-85, mean ~60 yrs
• 85% female
• NIHR BRC Bioresource
Potential Uses of Twins
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classical twin study – heritability
sib pair linkage/ association (GWAS) studies
rare variant association studies
gene- environment interactions
gene expression studies
epigenetics
microbiome/gut flora
functional genomics
pharmaco-genomics
metabolomics/glycomics
aging research
‘Omics’ resources in TwinsUK
Microbiome
Genomic
Epigenomic
Cellular
Cellular
System
Biochemical
System
Environment
System
Disease
Range of phenotypes – cardiovascular disease
Intermediate
endpoints
Metabolomic
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Biochemical (Fasting)
Physiologic /
functional / imaging
Clinical end points
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450 metabolites, proteins and >70 glycomics
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Glucose, insulin, Hb, platelet volume *
HDL-c, LDL-c, TG, TC, sCRP,*
homocysteine, adiponectin, leptin
Clotting factors (n=10) , clot structure and function
Cytokines- Il-1, IL-IR, Il-6, fibrinogen
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Actiheart monitors
Carotid arterial stiffness*
Carotid intima media thickness
Pulse wave velocity*
Retinal vessel imaging*
BMI *
DXA scans (body fat and lean)*
Blood pressure *
QT interval*
Lung function *
Questionnaire data
• Smoking, exercise, FFQ nutrition (EPIC) *
• SF36 quality of life scores), angina, family history, DVT.*
Hospital/Death
records
• MI, stroke, T2D
* Longitudinal measures up to 15 years apart
TwinsUK bio-resource
Biobank/ BRC
biocentre
Phenotypes
N=1000
GWAS
Expression
Multiple
tissues
TwinsUK
Record
linkage for
mortality and
morbidity
Nutrition
~6000
Methylome/
epigenetics
Gut
Microbiota
Collaborators
metabolomics
WG
sequence
International
Twin
Consortia
Twins : a multi-purpose
research resource
Dept of Twin Research&
Genetic Epidemiology
Division of Genetics
Kings College London
London
www.twinsuk.ac.uk
Heritability of Common Traits
Corneal thickness
FRECKLES
Myopia
ACNE
95%
90%
80
80
HEIGHT
OSTEOPOROSIS
80
75
DIABETES
OBESITY
BLOOD CLOTTING
BACK PAIN
IQ
ASTHMA , allergy
ARTHRITIS (OA)
CATARACT
Naevus count
Pain thresholds
70
70
70
65
65
60
60
60
55
55
Migraine
Varicose veins &HR
Menopause
Blood pressure
Menarche
50
50
50
45 %
40%
HIGH
LOW
GWAS – published on over 100 traits and 500 loci
Discordant Identicals:
Olivia & Isabella (ALL)
Hong et al Science. 2008 Jan 18;319(5861):336-9.
Identical but differentlow concordance rates for common disease in MZ twins
MZ twins – a natural RCT
Methlyation in Twin pairs
• MZ Twins show greater
concordance for total
methylation at different tissue
sites.
• Areas under most genetic
control are those close to
promotor regions of functional
importance.
Kaminsky et al Nature Genetics 2009
Buccal:
MZ= red, DZ=
blue
Epigenetics in MZ twins
Fraga et al PNAS 2005
Breast cancer discordant study
• 15 MZ pairs discordant
• 45,000 CpG sites arrayed, 403
differentially methylated (97% hypo)
• Many in known cancer genes
• DOK7 hypermethylation replicated in
further 22 twin pairs and tissue
samples
• Docking protein and activator of
receptor tyrosine kinases
Heyn et al. Carcinogenesis 2013;34:102-8
Pain sensitivity
• Chronic pain
– Common, expensive problem in NHS
– 50% heritable at most
– QST: quantitative sensory testing (HPST)
• 25 discordant MZ pairs (>2°difference)
– Epigenome-Wide Association Study (EWAS)
• Methylated DNA immunoprecipitation followed by
deep sequencing (MeDIP-seq)
– DMRs
• Methylation, MZ correlations, Allele-Specific
Methylation
Bell JT et al. Nat Commun. 2014; 5: 2978
TRPA1
• Ligate-gated ion channel found in
peripheral nociceptors
• Heat sensor in Drosophila
• Nominally increased expression in skin
with higher heat pain thresholds
• Suggest regulatory DNA methylation
region in a CpG-island shore of the
TRPA1 promoter
Measuring the environment: smoking
• Significant DNA demethylation at aryl
hydrocarbon receptor repressor (AHRR) gene
• Replicated widely (including TwinsUK)
• aryl hydrocarbon receptor (AHR)
– induction point for the xenobiotic pathway
– includes P450 enzymes (eg CYP1A1)
– responsible for the degradation of toxins (eg
polyaromatic carbons)
• Methylation changes found at birth in children of
smokers
Elliott et al. Clinical Epigenetics 2014, 6:4
Philibert et al. Clinical Epigenetics 2013, 5:19
Joubert et al. Environ Health Perspect 2012, 120:1425
Conclusions
• The twin bioresource is a flexible and powerful recallable
genomic resource
• Discordant MZ twin model with whole genome
methylation sequencing likely to be highly informative
– New disease mechanisms identified
• Consistent methylation changes with aging may be
biomarkers of mortality, but may also help us to
understand the aging process
– Many epigenetic changes direct cells towards “stem cell” status
and possibly increased malignancy
• Exciting data from smoking epigenetics suggest we may be
able to “measure” the environment effects more
accurately.
– Dietary factors increasing methylation (eg folate, methyl
donors) and reducing methylation (eg selenium, green tea
polyphenols) may be studied in better detail
NHS NIHR
Acknowledgements