Epigenetic correlates of human socioeconomic status Clyde Hertzman

Gradient in all Cause Mortality: UK Whitehall Study (1980s)

CHD Mortality - UK Whitehall Study

The Challenge of the Gradient ubiquitous in wealthy and majority world countries by income, education, or occupation cuts across a wide range of disease processes not explained by traditional risk factors replicates itself on new conditions as they emerge occurs among males and females ‘flattens up’ begins life as gradient in ‘developmental health’

Sensitive Periods in Early Brain DevelopmentVision High Low Years Habitual ways of responding Emotional control Symbol Peer social skills Numbers Hearing Graph developed by Council for Early Child Development (ref: Nash, 1997; Early Years Study, 1999; Shonkoff, 2000.) Pre-school yearsSchool years Language

Canada: % vulnerable by SES Source: NLSCY/UEY ; EDI % Vulnerable

Jamaica: % vulnerable by SES % Vulnerable SES % Vulnerable

Kosovo: % vulnerable by SES % Vulnerable

Life Course Impacts of Early Experiences 2 nd Decade 3 rd /4 th Decade 5 th /6 th Decade Old Age School Failure Teen Pregnancy Criminality Obesity Elevated Blood Pressure Depression Coronary Heart Disease Diabetes Premature Aging Memory Loss

Biological embedding occurs when experience gets under the skin and alters human biodevelopment; systematic differences in experience in different social environments lead to different biodevelopmental states; the differences are stable and long-term; they influence health, well-being, learning, and/or behaviour over the life course. Hypothesis: Biological embedding

Archeology of Biological Embedding Experience/BehaviorExperience/Behavior Gene Expression Cell/SynapseCell/Synapse Neural Circuitry

Shallow Archeology Candidate Systems HPA axis --- cortisol ANS system --- epinephrine/ne Prefrontal cortex Social affiliation --- amygdala/locus cereleus Immune function -- the ‘peripheral brain’

Candidate System: Prefrontal Cortex SES Differences by School Age

Deep Archeology ‘Social Epigenesis’ and other processes that can influence gene expression.

Biological Embedding: The ‘Meaney- Szyf Paradigm’ rat pups from high and low licking/suckling mothers cross-fostered to remove genetic effect differential qualities of nurturance occurs during sensitive period of brain development differential nurturance leads to epigenetic modification of key DNA regulatory loci through methylation

The ‘Meaney-Szyf Paradigm’ (cont’d) epigenetic modification leads to lifelong change in HPA axis response to stress this change affects learning and behaviour across the rat life course inter-generational transmission (high licked female pups become high licking mothers, and vice versa)

The Opportunity If early experience really does ‘get under the skin’ to influence brain and biological development through epigenetic processes, then: similar environments & experiences should leave a consistent set of epigenetic ‘marks’ on different populations, and/or create great opportunities for understanding gene-environment-epigenetic interplay. the variation in epigenetic marks in children from diverse environments (& experiences) globally should teach us a great deal about biological embedding.

SES, Life Course and Epigenesis: An Hypothesis Generating Study The opportunity: 1958 British Birth Cohort (>17,000 members at birth), with >4000 phenotypic variables collected at birth and 7 follow-ups, with fresh lymphocytes collected at age 45. The goal: to identify a full range of gene loci where experience may have become ‘biologically embedded’ through methylation. Done to date: examined >20,000 regulatory regions of 40 cohort members, sampled according to a factorial design, based upon extremes of SES in childhood and adulthood (also, abuse and maternal smoking)

The Team Population health/life course epidemiology: Clyde Hertzman, Chris Power Epigenetics: Moshe Szyf, Marcus Pembry Bio-informatics: Michael Hallett, Matt Suderman Laboratory: Nada Borghol

So far: 1252 loci differentially methylated according to childhood SES (smaller signatures for adult SES and social mobility) 794 loci differentially methylated by maternal smoking Approx loci differentially methylated by retrospective reports of abuse in childhood

1958 Cohort Replication Expression?? Gene analysis Exploit 4000 phenotypes with larger sample sizes

Consistency in different populations? The Wisconsin Study of Families and Work The BC GECKO Study: ‘On and Off-diagonal children’ in ‘On and Off-diagonal neighbourhoods’ Developing country studies

Mid- Brain affiliation/attachment PFC executive function/ impulsivity HPA stress response Abuse Chronic diseases Health behaviors Mental health Epigenome ExposureEndophenotypePhenotype Is this the way forward?

ExposureEpigenomeBiochemical /Biophysical Pathway Phenotype (Prenatal) Maternal Smoking Childhood Abuse Childhood SES Exposure Specific Pathways Common Pathways Exposure Specific Pathways Outcome(s)