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 Development

VisionVision

0 1 2 3 7654

High

Low

Years

Habitual ways of Habitual ways of respondingrespondingEmotional Emotional

controlcontrol

SymboSymboll

Peer social skillsPeer social skillsNumbersNumbers

HearingHearing

Graph developed by Council for Early Child Development (ref: Nash, 1997; Early Years Study, 1999; Shonkoff, 2000.)

Pre-school years School years

LanguaLanguagege

Canada: % vulnerable by SES

Source: NLSCY/UEY 1999-2000; EDI 1999-2000

% V

ulne

rabl

e

Jamaica: % vulnerable by SES%

Vul

nera

ble

SES

% V

ulne

rabl

e

Kosovo: % vulnerable by SES%

Vul

nera

ble

Life Course Impacts of EarlyExperiences

2nd Decade

3rd/4th Decade

5th/6th

DecadeOld Age

• School Failure

• Teen Pregnancy

• Criminality

• Obesity

• Elevated BloodPressure

• 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 EmbeddingArcheology of Biological EmbeddingArcheology of Biological EmbeddingArcheology of Biological Embedding

Experience/BehaviorExperience/BehaviorExperience/BehaviorExperience/Behavior

Gene ExpressionGene ExpressionGene ExpressionGene Expression

Cell/SynapseCell/SynapseCell/SynapseCell/Synapse

Neural CircuitryNeural CircuitryNeural CircuitryNeural Circuitry

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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. 4000 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

Exposure

Endophenotype

Phenotype

Is this the way forward?

Exposure

Epigenome

Biochemical/Biophysical Pathway

Phenotype

(Prenatal)Maternal Smoking

Childhood Abuse

Childhood SES

Exposure Specific Pathways

Common Pathways

Exposure Specific Pathways

Exposure Specific Pathways

Outcome(s)Outcome(s)

www.earlylearning.ubc.ca