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Epigenetics as a mediator of environmental influences on


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									 ALSPAC – The First 21 Years

      Epigenetics as a mediator of
environmental influences on disease risk

              Caroline Relton
       Institute of Genetic Medicine
         Newcastle University, UK
                                    The epigenome

Epigenetic patterns as environmental sensors

Epigenetic patterns as predictors of later health

                                                    Waterland Nutr Rev 2008

 Ng J, Barrett LM, Wong A, Kuh D, Davey Smith G, Relton CL. The role of
 longitudinal cohorts in epigenetic epidemiology: challenges and
 opportunities. Genome Biol, submitted 2012
Epigenetic mechanisms as a potential mediator
    of environmental influences on disease





    Accessible Resource for Integrated Epigenomic Studies

•    To undertake large scale DNA methylation profiling of 1,000 mother
     -child pairs at multiple time points across the life course
•    To undertake methylome sequencing of a sub-set of mother-child
•    To conduct tandem genome-wide methylation profiling and gene-
     expression profiling of several human tissues (fat, muscle, brain,
     liver, skin, cartilage, lymphocyte sub-sets, etc)
•    To construct a custom web-based portal to allow openly accessible
     browsing of genome-wide methylation data
•    To construct an interface to allow researchers to view ALSPAC data
     in relation to DNA methylation information
     Davey Smith, Relton, Ozanne, Evans, Ring, Gaunt, Reik, Wipat
A portal to integration and mining of ALSPAC ‘omics data

                                     ARIES Genome Browser
                      Epigenetic studies in ALSPAC
In progress                                          Planned
Alcohol in pregnancy and childhood                   Rheumatoid arthritis – Jon Tobias (University of
outcomes – Luisa Zuccolo (University of Bristol)     Bristol)

Conduct problem trajectories – Ted Barker            Lung function in children born preterm –
(Birkbeck College London)                            John Henderson (University of Bristol)

Eating disorders – Karen Mitchell (Boston            Endocrine disruptors – Sue Ring & Jean Golding
                                                     (University of Bristol)
                                                     Smoking in pregnancy and childhood
Insulin resistance – Hannah Elliott (Newcastle
                                                     outcomes – Jane Ng (Newcastle University)
                                                     Autism spectrum disorders – Beate St Pourcain,
Air pollution and lung function – Paolo Vineis       Jean Golding (University of Bristol) & Ezra Susser
and Paul Elliott (Imperial College London)           (Columbia University)
Childhood eczema – Lavinia Paternoster               Pregnancy induced hypertension – Rebecca
(University of Bristol)                              Richmond (University of Bristol)
Women’s health over the menopausal                   Cardiovascular disease – Nic Timpson
transition – Debbie Lawlor (University of Bristol)   (University of Bristol)
Childhood body composition – Caroline Relton         Breast cancer – Mona Jefferies (University of
(Newcastle University)                               Bristol)
Maternal weight gain in pregnancy – Eva              Cross-cohort comparisons – Multiple UK and
Morales (CREAL, Barcelona / Newcastle University)    international groups
                              Air pollution and lung function
      Children in top 5% of air pollution exposure are at increased risk of
      asthma or wheezing at age 7 (OR 1.44 [95% CI 1.03, 2.02] p=0.031)

       Does air pollution exert it’s influence on lung function through
       altering the epigenome?
                                                        158 CpG sites               325 CpG sites
                                                       associated with             associated with
                                                       lung function at            lung function at
                                                            age 7                       age 15

 178 CpG sites
associated with
  air pollution


                                               Age 7

                                                                          Age 15
                                         DNA methylation
    Maternal weight gain in pregnancy and childhood
    • Weight gain in pregnancy is increasing
        –Percentage of women gaining >40lb during
        pregnancy in the US (CDC 2008)

    •Greater weight gain in pregnancy is
    associated with
        – Complications of pregnancy
        – Adverse health outcomes in children
        – Greater adiposity in ALSPAC children at age
        9 (Fraser et al. 2010)
                                                        DNA methylation analysed in cord blood
    • Does greater maternal weight gain                 1505 CpG sites in 807 genes
    mediate its effects through altering fetal
    DNA methylation patterns?                           •Pre-pregnancy weight
                                                            No association with infant methylation
   MMP7, NFKB1, ABCC2, KCNK4, TRPM5                     •0-18 weeks weight gain
                                                            5 genes ↑ >5% methylation (p<0.01)
                                                        •19-28 weeks weight gain
 Vascular disease   Neurodevelopment       Insulin          1 gene ↑ >5% methylation (p<0.01)
PTB, Preeclampsia         PTB             sensitivity   •29 weeks-term weight gain
                                                            No association with infant methylation
Cord blood methylation and childhood body size
    Low              High
  BMI =16           BMI =26
FFM = 9.5 kg       FFM = 25 kg
Weight = 35 kg    Weight = 60 kg

                                          24 genes
                                   differentially expressed
                                Gene expression analysis
 PTBGS                            Clinical assessment

          Birth                                      Early adolescence
             0y                         9y
    DNA methylation analysis   Clinical assessment
          9/24 genes
   differentially methylated
             Using genetic information

                                    Diabetes 2012; 61(2): 391-400

Postnatal growth    TACSTD2      TACSTD2           Childhood adiposity
                   methylation   expression
      The impact of ALSPAC epigenetics research

•   ALSPAC will be the first longitudinal cohort study with
    comprehensive genome-wide DNA methylation profiling at multiple
    time points across the life course
•   These data can be used to address a wide range of hypotheses
    relating to exposures and health and development across the life
•   ALSPAC epigenetic data will produce the first population-based
    epigenetic resource mapping DNA methylation variation between
    individuals and across generations
•   Epidemiological methods will be developed using these data which
    can be applied by many other investigators
               Newcastle University                          University of Bristol
               Alix Groom                                    ALSPAC Study Team
               Hannah Elliott                                George Davey Smith
               Rosa Spencer                                  Debbie Lawlor
               Kate Potter                                   Sue Ring
               Eva Morales                                   Wendy McArdle
               James McConnell                               Nic Timpson
               Jane Ng                                       David Evans
               Laura Barrett                                 Kate Northstone
               Julie Coaker                                  Beate St Pourcain
               John Mathers                                  John Henderson
               Nick Embleton                                 Lynn Molloy
               Neil Wipat                                    Luisa Zuccolo
                                                             Jon Tobias
                                                             Dara O’Hare
Newcastle NIHR Biomedical Research Centre in Ageing and Age Related Disease
 ALSPAC – The First 21 Years

      Epigenetics as a mediator of
environmental influences on disease risk

              Caroline Relton
       Institute of Genetic Medicine
         Newcastle University, UK

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