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Hair Color is a Heritable Trait
Plan for Today
• No clicker review
• Lecture on Nature & Nurture
• Take-home critical thinking questions
• No class on Thursday
PSYC 210:
The nature & nurture of T&P
Part 1
AJ Shackman
March 25, 2014
Conceptual Roadmap for Today, 1
Temperament is often conceptualized as ‘biological’
and ‘inherited.’
e.g., The Malfoys
But just how heritable is T&P? Does it ‘breed true?’
Students?
Conceptual Roadmap for Today, 2
We have been trained (brain-washed?) by our
culture to think in terms of heritability.
To blame a family’s or a race’s genes.
But what exactly is heritability? What are the
limitations of heritability measures?
What are the prospects for linking heritable traits
(T&P) to discrete systems in the brain?
Conceptual Roadmap for Today, 2
We have been trained (brain-washed?) by our
culture to think in terms of heritability.
To blame a family’s or a race’s genes.
But what exactly is heritability? What are the
limitations of heritability measures?
What are the prospects for linking heritable traits
(T&P) to discrete brain mechanisms?
4 Essential Lessons
About the Nature & Nurture of T&P
Some Key Take Homes
T&P Reflect Both Nature (Genes) and Nurture
(Environment/Experience)
Some Key Take Homes
T&P Reflect Both Nature (Genes) and Nurture
(Environment/Experience)
• “Twin, adoption and family studies have convincingly shown
that each of the FFM personality dimensions is heritable, with
heritability estimates ranging between 33% and 65%” de Moor
et al. Mol Psychiatry 2012; see also Bouchard & Loehlin Behav
Gen 2001;
• E.g., ~45% of the variance in N and E is heritable (Vinkhuyzen
et al Transl Psychiatry 2012), similar to Pilia et al PLOS Gen
2006 and Turkheimer et al Ann Rev Psychol 2014
• A bit more than half the variation in T&P is NURTURE
• Therefore, trait-like individual differences in T&P are not
biological destiny!
Some Key Take Homes
T&P Reflect Both Nature (Genes) and Nurture
(Environment/Experience)
• “Twin, adoption and family studies have convincingly shown
that each of the FFM personality dimensions is heritable, with
heritability estimates ranging between 33% and 65%” de Moor
et al. Mol Psychiatry 2012; see also Bouchard & Loehlin Behav
Gen 2001;
• E.g., ~45% of the variance in N and E is heritable (Vinkhuyzen
et al Transl Psychiatry 2012), similar to Pilia et al PLOS Gen
2006 and Turkheimer et al Ann Rev Psychol 2014
• A bit more than half the variation in T&P is NURTURE
• Therefore, trait-like individual differences in T&P are not
biological destiny!
Some Key Take Homes
Genes (nature) can influence environments (nurture)
Draco Malfoy’s Genes
(DNA)
Draco Malfoy, Across Early Development
Students — What exactly is Draco’s ‘environment’ ? What are some likely key elements?
Some Key Take Homes
Genes (nature) can influence environments (nurture)
Draco Malfoy’s Genes
(DNA)
Draco Malfoy, Across Early Development
Students — What exactly is Draco’s ‘environment’ ? What are some likely key elements?
Some Key Take Homes
Genes (nature) can influence environments (nurture)
• Many measures of “the environment” are genetically
determined (heritable)
• Same genes can cause both environment and personality
(or personality via environment)
e.g., “Genes for NE/N”  child-rearing/nurture, peers
e.g., “Genes for NE/N”  life-events, such as divorce
• T&P accounts for >30% of the heritable influence on divorce
risk
Some Key Take Homes
Genes (nature) can influence environments (nurture)
• Many measures of “the environment” are genetically
determined (heritable)
• Same genes can cause both environment and personality
(or personality via environment)
e.g., “Genes for NE/N”  child-rearing/nurture, peers
e.g., “Genes for NE/N”  life-events, such as divorce
• T&P accounts for >30% of the heritable influence on divorce risk
Some Key Take Homes
Remember, when a measure of “the environment”
and T&P are correlated, 2 causal pathways are
possible
T&P  Environment
e.g., child’s T&P evokes a style of nurturing
-or-
Environment  T&P
e.g., chronic stress increases N/NE
Some Key Take Homes
Remember, when a measure of “the environment”
and T&P are correlated, 2 causal pathways are
possible
T&P  Environment
e.g., child’s T&P evokes a style of nurturing
-or-
Environment  T&P
e.g., chronic stress increases N/NE
Some Key Take Homes
Remember, when a measure of “the environment”
and T&P are correlated, 2 causal pathways are
possible
T&P  Environment
e.g., child’s T&P evokes a style of nurturing
-or-
Environment  T&P
e.g., chronic stress increases N/NE
Some Key Take Homes
‘Nature’ is not static
Some Key Take Homes
‘Nature’ is not static
• Genetic influences (heritability) can change over
development
• Individuals gain increased instrumental control over
the environment (e.g., routine, occupation, spouse)
• Over time, there is more opportunity for biases and
dispositions (T&P) to influence; cumulative impact
What exactly is heritability?
“The *modern+ concept of heritability…was introduced…nearly a century ago.
Despite continuous misunderstandings and controversies…heritability remains
key to the prediction of disease risk in medicine”
What is heritability (h2)
What is heritability (h2)
• A single number indicating the % of variation
between individuals in a population due to
genotype; a ratio of two variances
• Total Phenotypic variance (PV) = Genotypic
Variance (GV) + Environmental Variance (EV)
• Heritability = GV / PV = fraction of total variance
in a trait predicted by the pedigree
What is heritability (h2)
• A single number indicating the % of variation
between individuals in a population due to
genotype; a ratio of two variances
• Total Phenotypic variance (PV) = Genotypic
Variance (GV) + Environmental Variance (EV)
• Heritability = GV / PV = fraction of total variance
in a trait predicted by the pedigree
What is heritability (h2)
• A single number indicating the % of variation
between individuals in a population due to
genotype; a ratio of two variances
• Total Phenotypic variance (PV) = Genotypic
Variance (GV) + Environmental Variance (EV)
• Heritability = GV / PV = fraction of total variance
in a trait predicted by the pedigree
How well can you predict Ginny’s hair
color knowing that she is related to
other members of the Weasley clan?
Heritability (h2) estimates can mislead
• If non-trivial, ignoring G*E interactions deflates
h2 (e.g., MDD is not very heritable)
Heritability (h2) estimates can mislead
• H2 usually ignores G-E correlations
– the genotype and the phenotype are correlated
– e.g., high IQ parents providing enriched environment for offspring;
cattle fed in accord with milk production
• H2 usually ignores G*E interactions (focusing on additive ME’s)
– the effect of the genotype depends on the environment
– e.g., stress x serotonin transporter gene = depression
• If non-trivial, ignoring G-E correlations inflates h2 (e.g., IQ is
really, really heritable)
• If non-trivial, ignoring G*E interactions deflates h2 (e.g., MDD is
not very heritable)
Heritability (h2) estimates can mislead
• H2 usually ignores G-E correlations
– the genotype and the phenotype are correlated
– e.g., high IQ parents providing enriched environment for offspring;
cattle fed in accord with milk production
• H2 usually ignores G*E interactions (focusing on additive ME’s)
– the effect of the genotype depends on the environment
– e.g., stress x ‘risky’ serotonin transporter gene = depression (MDD)
• If non-trivial, ignoring G-E correlations inflates h2 (e.g., IQ is
really, really heritable)
• If non-trivial, ignoring G*E interactions deflates h2 (e.g., MDD is
not very heritable)
Heritability (h2) estimates can mislead
• H2 usually ignores G-E correlations (focusing on additive ME’s)
– the genotype and the phenotype are correlated
– e.g., high IQ parents providing enriched environment for offspring;
cattle fed in accord with milk production)
• H2 usually ignores G*E interactions (focusing on additive ME’s)
– the effect of the genotype depends on the environment
– e.g., stress x ‘risky’ serotonin transporter gene = depression (MDD)
• Ignoring G-E correlations inflates h2 (IQ is really, really
heritable)
• Ignoring G*E interactions deflates h2 (MDD is not very
heritable)
Heritability (h2) estimates can mislead
H2 ignores G-G interactions
• Over-estimates total heritability
• Growing evidence that the impact of particular
variants is highly dependent on ‘genetic context’
• Effects depend upon what other genes are doing
• X
Huang et al PNAS 2012
Heritability (h2) is not absolute
Heritability (h2) is not absolute
• Ratio (PV/GV): Made larger by diversifying the genetic variance &/or
minimizing environmental effects
• Sample specific, as with other correlations
• Social control tends to constrain heritability, whereas heritability is
generally higher under conditions of low social constraint
e.g., Differences in disinhibition (partying, drinking, and multiple
sex partners) are not heritable among those raised in a
conservative religious environment
No variation
e.g., Heritability of smoking in females rose over time as it became
more socially acceptable, with no change in men
• h2 can dynamically change over lifespan
Heritability (h2) is not absolute
• Ratio (PV/GV): Made larger by diversifying the genetic variance &/or
minimizing environmental effects
• Sample specific, as with other correlations
• Social control tends to constrain heritability, whereas heritability is
generally higher under conditions of low social constraint
e.g., Differences in disinhibition (partying, drinking, and multiple
sex partners) are not heritable among those raised in a
conservative religious environment
No variation
e.g., Heritability of smoking in females rose over time as it became
more socially acceptable, with no change in men
• h2 can dynamically change over lifespan
Heritability (h2) is not absolute
• Ratio (PV/GV): Made larger by diversifying the genetic variance &/or
minimizing environmental effects
• Sample specific, as with other correlations
• Social control tends to constrain heritability, whereas heritability is
generally higher under conditions of low social constraint
e.g., Differences in disinhibition (partying, drinking, and multiple
sex partners) are not heritable among those raised in a
conservative religious environment
Variation
e.g., Heritability of smoking in females rose over time as it became
more socially acceptable, with no change in men
• h2 can dynamically change over lifespan
Heritability (h2) is not absolute
• Ratio (PV/GV): Made larger by diversifying the genetic variance
&/or minimizing environmental effects
• Sample specific, as with other correlations
• Social control reduces heritability; heritability is generally
higher under conditions of low social constraint
e.g., Differences in disinhibition (partying, drinking, and
multiple sex partners) are not heritable among those raised
in a conservative religious environment
e.g., Heritability of smoking in females rose over time as it
became more socially acceptable, with no change in men
• h2 can dynamically change over lifespan
Heritability (h2) is not absolute
• Ratio (PV/GV): Made larger by diversifying the genetic variance
&/or minimizing environmental effects
• Sample specific, as with other correlations
• Social control reduces heritability; heritability is generally
higher under conditions of low social constraint
e.g., Differences in disinhibition (partying, drinking, and
multiple sex partners) are not heritable among those raised
in a conservative religious environment
e.g., Heritability of smoking in females rose over time as it
became more socially acceptable, with no change in men
• h2 can dynamically change over lifespan
4 common misconceptions
4 common misconceptions
Heritability is the % of a phenotype that is passed
on to the next generation. Wrong!
• E.g., ~40% of the variation in T&P is passed on –
no!
Students – Why is this wrong?
• Genes are passed on, not phenotypes/traits
4 common misconceptions
Heritability is the % of a phenotype that is passed
on to the next generation. Wrong!
• E.g., ~40% of the variation in T&P is passed on –
no!
• Genes are passed on, not phenotypes/traits
4 common misconceptions
40% of Alex’s T&P is inherited (nature) and 60% is
environmental (nurture). Wrong!
• h2 reflects the proportion of variation between
individuals (Alex vs. Jee vs. Hannah) in a
Students – Why is this wrong?
population that is influenced by genetic factors.
• h2 describes the population variation, not
individuals (Alex) within that population
4 common misconceptions
40% of Alex’s T&P is inherited (nature) and 60% is
environmental (nurture). Wrong!
• h2 reflects the proportion of variation between
individuals (Alex vs. Jee vs. Hannah) in a
population that is influenced by genetic factors.
• h2 describes the population variation, not
individuals (Alex) within that population
4 common misconceptions
High heritability implies genetic determination or destiny.
Wrong!
• High heritability means that most of the variation that is
observed is caused by genetic variation
• That is, pedigree is a good predictor of a trait in a particular pop
• Does not mean that the phenotype is fixed once we know the
genotype, because the environment can markedly alter the
phenotype
It is unavoidable.
It is youryet
destiny.
You, like
• E.g., 80% of the variation in height
is heritable,
people
your father, are now mine.
around the world have grown
much taller in the face of
improved nutrition and medical care
Students – Why is this wrong?
4 common misconceptions
High heritability implies genetic determination or destiny.
Wrong!
• High heritability means that most of the variation that is
observed is caused by genetic variation
• That is, pedigree is a good predictor of a trait in a particular pop
• Does not mean that the phenotype is fixed once we know the
genotype, because the environment can markedly alter the
phenotype
• E.g., 80% of the variation in height is heritable, yet people
around the world have grown much taller in the face of
improved nutrition and medical care
4 common misconceptions
High heritability implies genetic determination or destiny.
Wrong!
• High heritability means that most of the variation that is
observed is caused by genetic variation
• That is, pedigree is a good predictor of a trait in a particular pop
• Does not mean that the mean phenotype is fixed, because the
environment can markedly alter the mean phenotype
• E.g., 80% of the variation in height is heritable, yet people
around the world have grown much taller in the past century
because of changes in the environment (improved nutrition and
medical care)
4 common misconceptions
High heritability implies genetic determination or destiny.
Wrong!
• High heritability means that most of the variation that is
observed is caused by genetic variation
• That is, pedigree is a good predictor of a trait in a particular pop
• Does not mean that the mean phenotype is fixed, because the
environment can markedly alter the mean phenotype
• E.g., 80% of the variation in height is heritable, yet people
around the world have grown much taller in the past century
because of changes in the environment (improved nutrition and
medical care)
What Does 80% Heritable Even Mean?
4 common misconceptions
High heritability implies genetic determination or
destiny. Wrong!
• Furthermore, “80%” is misleading:
– e.g., for adult human height
• h2 = 0.8
• Pop SD =~7 cm
– the SD of height in adult offspring around the mean value
of their parents is ~5.4 cm
– which is only a bit less than the SD in the population
• Tall parents on average have tall children, but with
considerable variation around the parental mean
4 common misconceptions
High heritability implies genetic determination or
destiny. Wrong!
• Furthermore, “80%” is misleading:
– e.g., for adult human height
• h2 = 0.8
• Pop SD =~7 cm
– the SD of height in adult offspring around the mean value
of their parents is ~5.4 cm
– which is only a bit less than the SD in the population
• Tall parents on average have tall children, but with
considerable variation around the parental mean
4 common misconceptions
Heritability is informative about the nature of mean differences across groups or
time. Wrong!
• Heritability is not informative about mean changes across groups or time
• Height and IQ are highly heritable
• Height and IQ have both increased around the world over the past century
• 1850: US white men were ~9 cm taller than Dutch males. USA! USA! USA!
• 2000: US white men were taller than ever before but are now about ~5 cm
shorter than Dutch men. Go Orange!
• This reflects changes in the environment
• Take home: High heritability should not deter the development of interventions
4 common misconceptions
Heritability is informative about the nature of mean differences across groups or
time. Wrong!
• Heritability is not informative about mean changes across groups (e.g., races) or
time (e.g., birth cohorts)
• E.g., height and IQ are highly heritable, but they are not fixed
• Height and IQ have both increased around the world over the past century
• 1850: US white men were ~9 cm taller than Dutch males. USA! USA! USA!
• 2000: US white men were taller than ever before but are now about ~5 cm
shorter than Dutch men. Go Orange!
• This reflects changes in the environment (nutrition, healthcare)
• Take home: High heritability should not deter the development of interventions
4 common misconceptions
Heritability is informative about the nature of mean differences across groups or
time. Wrong!
• Heritability is not informative about mean changes across groups (e.g., races) or
time (e.g., birth cohorts)
• E.g., height and IQ are highly heritable, but they are not fixed
• Height and IQ have both increased around the world over the past century
• 1850: US white men were ~9 cm taller than Dutch males. USA! USA! USA!
• 2000: US white men were taller than ever before but are now about ~5 cm
shorter than Dutch men. Go Orange!
• This reflects changes in the environment (nutrition, healthcare)
• Take home: High heritability should not deter the development of interventions
Family, twin and adoption studies (FTA)
show that all psychiatric disorders
aggregate in families and are heritable
- Things that relatives share (genes, diet, peers, SES, toxin exposure)
are important for etiology
- Genes in aggregate have important roles in etiology
- FTA studies are correlational; no insight into underlying molecular
or neural mechanisms
- Kendler notes that because Dx (and T&P traits) are artificial
categories that do not “carve nature at the joints” (cf. endo
lecture), showing heritability of The Disorder does not imply a
coherent or unified underlying biological cause
Family, twin and adoption studies (FTA)
show that all psychiatric disorders
aggregate in families and are heritable
- Things that relatives share (genes, diet, peers, SES, toxin exposure)
are important for etiology
- Genes in aggregate have important roles in etiology
- FTA studies are correlational; no insight into underlying molecular
or neural mechanisms
- Kendler notes that because Dx (and T&P traits) are artificial
categories that do not “carve nature at the joints” (cf. endo
lecture), showing heritability of The Disorder or The Trait does not
imply a single coherent or unified underlying biological cause
Family, twin and adoption studies (FTA)
show that all psychiatric disorders
aggregate in families and are heritable
- Things that relatives share (genes, diet, peers, SES, toxin exposure)
are important for etiology
- Genes in aggregate have important roles in etiology
- FTA studies are correlational; no insight into underlying molecular
or neural mechanisms
- Kendler notes that because diagnoses (like T&P traits) are artificial
categories that do not “carve nature at the joints”
- Showing heritability of The Disorder or The Trait does not imply a
single coherent or unified underlying biological cause
What are the long-term prospects
for mapping the chain from genetic
variants to neural intermediates to traits,
such as N/NE, E/PE, or C/SC?
Genome
Intermediate Phenotype
Traits (Evildoing)
Kendler offers two metaphors,
framed in terms of psychiatric disorders
But these metaphors pertain to
other traits, such as T&P,
just as well
Kendler’s Broken Glass Metaphor
Imagine that one key mind–brain circuit (for example, the ‘grief’ system) is like a glass.
The total strength of the glass—the resilience of the system—reflects an emergent property of
many, many genes acting together that constructs a glass that is either stress sensitive or
resistant.
Now imagine that we have a machine deliver a hammer-blow (aka a critical life stressor) such
that a set percentage of the glasses break (aka develop illness).
Kendler’s Broken Glass Metaphor
Imagine that one key mind–brain circuit (for example, the ‘grief’ system) is like a glass.
The total strength of the glass—the resilience of the system—reflects an emergent property of
many, many genes acting together that constructs a glass that is either stress sensitive or
resistant.
Now imagine that we have a machine deliver a hammer-blow (aka a critical life stressor) such
that a set percentage of the glasses break (aka develop illness).
Kendler’s Broken Glass Metaphor
Ugly Scenario
Each glass that breaks shatters in its own unique way.
If this is true, we shall have a very hard time getting a single reliable set of genes, there are too
many different ways for the glass to break.
Kendler’s Broken Glass Metaphor
Ugly Scenario
Perhaps there are too many ways for the human brain to produce symptoms/signs of
psychiatric disorders (e.g., sad mood, auditory hallucinations) for a limited number of
biologically coherent pathways to emerge from the 1000’s of genes that make small
contributions to risk.
If so, then a genetic mess is a plausible outcome because genes are the ‘wrong level’ for trying
to understand the biological mechanisms that cause the trait (T&P or Dx)
Kendler’s Broken Glass Metaphor
Good Scenario:
This would occur if, in all humans, the glass developed with one deep notch in it—one weak
point constructed by a small coordinated gene network.
Each time the glass was struck, if it broke, it would (nearly) always break along the notch.
Here, our large-scale studies would get a consistent strong signal from those sets of genes
which knitted the glass around the notch—the ‘weak link’ in the system.
Kendler’s Broken Glass Metaphor
Intermediate Scenarios:
There might be a few, moderately stable small notches over parts of the glass. However, most
of the glass would shatter in a random manner.
Or
There might be a modest number of possible notches with individuals weak at none, one, or
more than one. This would produce sufficient consistency in a large sample study to detect the
gene networks responsible for the various notches with some reproducibility.
These intermediate scenarios are more likely than The Good or The Ugly Scenarios
Kendler’s Jet Mechanic Metaphor
Kendler’s Jet Mechanic Metaphor
Your job is to ‘diagnose’ the problems with a 747 where the pilot complained that ‘the plane
was not flying well.’
A 747 has six million parts, about the number of common variants in the human genome.
You carefully screen all 6M parts and identify 50 broken ones
Kendler’s Jet Mechanic Metaphor
Your job is to ‘diagnose’ the problems with a 747 where the pilot complained that ‘the plane
was not flying well.’
A 747 has six million parts, about the number of common variants in the human genome.
You carefully screen all 6M parts and identify 50 broken ones
Ugly Scenario: The 50 parts come from entirely different systems of the aircraft. You cannot see
any pattern. The broken parts do not all contain the same kind of components, come from the
same supplier or originate from the same kind of system. You are stumped.
Kendler’s Jet Mechanic Metaphor
Your job is to ‘diagnose’ the problems with a 747 where the pilot complained that ‘the plane
was not flying well.’
A 747 has six million parts, about the number of common variants in the human genome.
You carefully screen all 6M parts and identify 50 broken ones
Ugly Scenario: The 50 parts come from entirely different systems of the aircraft. You cannot see
any pattern. The broken parts do not all contain the same kind of components, come from the
same supplier or originate from the same kind of system. You are stumped.
Good Scenario: You realize that although spread out over several areas of the plane and
reflecting different subsystems, all 50 broken parts play an important role in one functional
system in the airplane—the functioning of the wing flaps. The flap fixers (Big Pharma) are
ecstatic.
Kendler’s Jet Mechanic Metaphor
Your job is to ‘diagnose’ the problems with a 747 where the pilot complained that ‘the plane
was not flying well.’
A 747 has six million parts, about the number of common variants in the human genome.
You carefully screen all 6M parts and identify 50 broken ones
Ugly Scenario: The 50 parts come from entirely different systems of the aircraft. You cannot see
any pattern. The broken parts do not all contain the same kind of components, come from the
same supplier or originate from the same kind of system. You are stumped.
Good Scenario: You realize that although spread out over several areas of the plane and
reflecting different subsystems, all 50 broken parts play an important role in one functional
system in the airplane—the functioning of the wing flaps. The flap fixers (Big Pharma) are
ecstatic.
Intermediates: 40 of the 50 broken parts come from 3 unrelated systems
Or
You discover 4 sets of broken parts—3 to 5 parts each—that reflect individual sub-systems. But
most of the parts seem random and cannot be meaningfully linked together in any useful way.
These latter 2 scenarios are more likely than The Good or The Ugly ones.
Some Take Homes on Nature/Nurture
1.
T&P traits (~45%) and psychiatric disorders are heritable
2.
Genes are passed down, not phenotypes. Heritability refers to the % of between-individual variation
predictable from pedigree, not the % of a trait within an individual that is nature vs. nurture.
3.
Researchers and the public tend to mis-read the implications of heritability:
- Highly heritable traits (e.g., height) can be highly amenable to intervention. Heritability does
not imply genetic determinism
- Heritability is probabilistic: Tall parents, tall kids on average but substantial spread from kid
to kid
4. Things that relatives share (genes, diet, peers, SES, toxin exposure) are important for etiology of T&P as
well as Dx
5. Recent GWAS have shown some success, recapitulating what we believed based on FTA studies
6. Genes in aggregate have important roles in etiology, but the underlying biological mechanisms remain
unclear (both in terms of specific genetic polymorphisms and particular neural systems)
7. Kendler’s metaphors: The Broken Glass, and, The Jet Mechanic. Long-term prospects for understanding
strongly depend on the nature of the mapping from gene to brain to phenotype, which is unknown.
8. Switching from heterogeneous, trait-like superfactors and Dx’s to simpler endophenotypes may prove
helpful.
Some Take Homes on Nature/Nurture
1.
T&P traits (~45%) and psychiatric disorders are heritable
2.
Genes are passed down, not phenotypes. Heritability refers to the % of between-individual variation
predictable from pedigree, not the % of a trait within an individual that is nature vs. nurture.
3.
Researchers and the public tend to mis-read the implications of heritability:
- Highly heritable traits (e.g., height) can be highly amenable to intervention. Heritability does
not imply genetic determinism
- Heritability is probabilistic: Tall parents, tall kids on average but substantial spread from kid
to kid
4. Things that relatives share (genes, diet, peers, SES, toxin exposure) are important for etiology of T&P as
well as Dx
5. Recent GWAS have shown some success, recapitulating what we believed based on FTA studies
6. Genes in aggregate have important roles in etiology, but the underlying biological mechanisms remain
unclear (both in terms of specific genetic polymorphisms and particular neural systems)
7. Kendler’s metaphors: The Broken Glass, and, The Jet Mechanic. Long-term prospects for understanding
strongly depend on the nature of the mapping from gene to brain to phenotype, which is unknown.
8. Switching from heterogeneous, trait-like superfactors and Dx’s to simpler endophenotypes may prove
helpful.
Some Take Homes on Nature/Nurture
1.
T&P traits (~45%) and psychiatric disorders are heritable
2.
Genes are passed down, not phenotypes. Heritability refers to the % of between-individual variation
predictable from pedigree, not the % of a trait within an individual that is nature vs. nurture.
3.
Researchers and the public tend to mis-read the implications of heritability:
- Highly heritable traits (e.g., height) can be highly amenable to intervention. Heritability does
not imply genetic determinism
- Heritability is probabilistic: Tall parents, tall kids on average but substantial spread from kid
to kid
4. Things that relatives share (genes, diet, peers, SES, toxin exposure) are important for etiology of T&P as
well as Dx
5. Recent GWAS have shown some success, recapitulating what we believed based on FTA studies
6. Genes in aggregate have important roles in etiology, but the underlying biological mechanisms remain
unclear (both in terms of specific genetic polymorphisms and particular neural systems)
7. Kendler’s metaphors: The Broken Glass, and, The Jet Mechanic. Long-term prospects for understanding
strongly depend on the nature of the mapping from gene to brain to phenotype, which is unknown.
8. Switching from heterogeneous, trait-like superfactors and Dx’s to simpler endophenotypes may prove
helpful.
Some Take Homes on Nature/Nurture
1.
T&P traits (~45%) and psychiatric disorders are heritable
2.
Genes are passed down, not phenotypes. Heritability refers to the % of between-individual variation
predictable from pedigree, not the % of a trait within an individual that is nature vs. nurture.
3.
Researchers and the public tend to mis-read the implications of heritability:
- Highly heritable traits (e.g., height) can be highly amenable to intervention. Heritability does
not imply genetic determinism
- Heritability is probabilistic: Tall parents, tall kids on average but substantial spread from kid
to kid
4. Things that relatives share (genes, diet, peers, SES, toxin exposure) are important for etiology of T&P as
well as Dx
5. Recent GWAS have shown some success, recapitulating what we believed based on FTA studies
6. Genes in aggregate have important roles in etiology, but the underlying biological mechanisms remain
unclear (both in terms of specific genetic polymorphisms and particular neural systems)
7. Kendler’s metaphors: The Broken Glass, and, The Jet Mechanic. Long-term prospects for understanding
strongly depend on the nature of the mapping from gene to brain to phenotype, which is unknown.
8. Switching from heterogeneous, trait-like superfactors and Dx’s to simpler endophenotypes may prove
helpful.
Some Take Homes on Nature/Nurture
1.
T&P traits (~45%) and psychiatric disorders are heritable
2.
Genes are passed down, not phenotypes. Heritability refers to the % of between-individual variation
predictable from pedigree, not the % of a trait within an individual that is nature vs. nurture.
3.
Researchers and the public tend to mis-read the implications of heritability:
- Highly heritable traits (e.g., height) can be highly amenable to intervention. Heritability does
not imply genetic determinism
- Heritability is probabilistic: Tall parents, tall kids on average but substantial spread from kid
to kid
4. Things that relatives share (genes, diet, peers, SES, toxin exposure) are important for etiology of T&P as
well as Dx
5. Genes in aggregate have important roles in etiology, but the underlying biological mechanisms remain
unclear (both in terms of specific genetic polymorphisms and particular neural systems)
6. Kendler’s metaphors: The Broken Glass, and, The Jet Mechanic. Long-term prospects for understanding
strongly depend on the nature of the mapping from gene to brain to phenotype, which is unknown.
7. Switching from heterogeneous, trait-like superfactors and Dx’s to simpler endophenotypes may prove
helpful.
Some Take Homes on Nature/Nurture
1.
T&P traits (~45%) and psychiatric disorders are heritable
2.
Genes are passed down, not phenotypes. Heritability refers to the % of between-individual variation
predictable from pedigree, not the % of a trait within an individual that is nature vs. nurture.
3.
Researchers and the public tend to mis-read the implications of heritability:
- Highly heritable traits (e.g., height) can be highly amenable to intervention. Heritability does
not imply genetic determinism
- Heritability is probabilistic: Tall parents, tall kids on average but substantial spread from kid
to kid
4. Things that relatives share (genes, diet, peers, SES, toxin exposure) are important for etiology of T&P as
well as Dx
5. Genes in aggregate have important roles in etiology, but the underlying biological mechanisms remain
unclear (both in terms of specific genetic polymorphisms and particular neural systems)
6. Kendler’s metaphors: The Broken Glass, and, The Jet Mechanic. Long-term prospects for understanding
strongly depend on the nature of the mapping from gene to brain to phenotype, which is unknown.
7. Switching from heterogeneous, trait-like superfactors and Dx’s to simpler endophenotypes may prove
helpful.
Some Take Homes on Nature/Nurture
1.
T&P traits (~45%) and psychiatric disorders are heritable
2.
Genes are passed down, not phenotypes. Heritability refers to the % of between-individual variation
predictable from pedigree, not the % of a trait within an individual that is nature vs. nurture.
3.
Researchers and the public tend to mis-read the implications of heritability:
- Highly heritable traits (e.g., height) can be highly amenable to intervention. Heritability does
not imply genetic determinism
- Heritability is probabilistic: Tall parents, tall kids on average but substantial spread from kid
to kid
4. Things that relatives share (genes, diet, peers, SES, toxin exposure) are important for etiology of T&P as
well as Dx
5. Genes in aggregate have important roles in etiology, but the underlying biological mechanisms remain
unclear (both in terms of specific genetic polymorphisms and particular neural systems)
6. Kendler’s metaphors: The Broken Glass, and, The Jet Mechanic. Long-term prospects for understanding
strongly depend on the nature of the mapping from gene to brain to phenotype, which is unknown.
7. Switching from heterogeneous, trait-like superfactors and Dx’s to simpler endophenotypes may prove
helpful.
Critical Thinking Questions
1. Have you ever blamed your T&P on your genes? Has anyone else
ever judged or stereotyped your temperament, personality, or
character based on their assumptions about your genes? How does
the material discussed in class today change how you think about
this?
2. What are the implications of your newfound understanding of
heritability for interventions aimed at decreasing N/NE (or
childhood BI) or enhancing C/SC? If your views have changed,
describe how.
The End
Extra Slides
The Neurogenetic Strategy
Link genetic variation (polymorphisms) to variation in brain structure and function (MRI)
Address how genes influence behavior – heritability does not address mechanism!
- by correlating genetic variation with intermediate biological phenotypes (e.g., amygdala
activation), we can discover testable mechanisms for genetic influence on behavior
Address the molecular mechanisms linking genes to brain to behavior
- it’s hard to directly measure neurochemistry (e.g., serotonin levels in the amygdala) in humans
- If we measure a genetic polymorphism with a known function (e.g., serotonin transporter SNP)
- and we are willing to make some assumptions (differences in the SNP have predictable effects
on gene expression and ultimately serotonin levels in the amygdala)
- then we can use genetic variation (polymorphisms), which we can noninvasively measure in
humans, as a proxy for individual differences in neurochemistry (serotonin in the amygdala),
The Neurogenetic Strategy
Link genetic variation (polymorphisms) to variation in brain structure and function (MRI)
Address how genes influence behavior – heritability does not address mechanism!
- by correlating genetic variation with intermediate biological phenotypes (e.g., amygdala
activation), we can discover testable mechanisms for genetic influence on behavior
Address the molecular mechanisms linking genes to brain to behavior
- it’s hard to directly measure neurochemistry (e.g., serotonin levels in the amygdala) in humans
- If we measure a genetic polymorphism with a known function (e.g., serotonin transporter)
- and we are willing to make some assumptions (differences in the poly. have predictable effects
on gene expression and ultimately serotonin levels in the amygdala)
- then we can use genetic variation (polymorphisms), which we can noninvasively measure in
humans, as a proxy for individual differences in neurochemistry (serotonin in the amygdala),
Quick Genetics Tutorial
- DNA is organized into chromosomes, the vectors of heredity
- Human cells have 23 pairs of chromosomes (46 / cell), one pair
‘descended’ from mom and one from dad
- Gene: a region of DNA/RNA sequence, corresponding to a unit of
inheritance or single basic instruction
- Allele: a variant of a gene
- Genes are transcribed to RNA and
used to code protein synthesis, e.g.,
build neurons, axons, transporters,
vesicles, neurochemicals, myelin, etc.
Seminal Example: Amygdala & 5-HTTLPR
- Threat-related amygdala reactivity is correlated with variation in the
serotonin-transporter linked polymorphic region (5-HTTLPR) on the
SLC6A4 gene
- “S allele is bad:” Individuals with the less transcriptionally-efficient
short allele (fewer transporter proteins available to clear serotonin
from the synapse) show heightened threat-related amygdala
reactivity relative to individuals with the long allele
- Gene  Amygdala: Meta-analyses suggest that the 5-HTTLPR
genotype accounts for 2-5 of the variance in amygdala reactivity
- Gene  Amygdala  MDD: Evidence that these genetically
conferred differences in amygdala reactivity mediate some of the
association between the 5-HTTLPR polymorphism and depression
Seminal Example: Amygdala & 5-HTTLPR
- Threat-related amygdala reactivity is correlated with variation in the
serotonin-transporter linked polymorphic region (5-HTTLPR) on the
SLC6A4 gene
- “S allele is bad:” Individuals with the less transcriptionally-efficient
short allele (fewer transporter proteins available to clear serotonin
from the synapse) show heightened threat-related amygdala
reactivity relative to individuals with the long allele
- Gene  Amygdala: Meta-analyses suggest that the 5-HTTLPR
genotype accounts for 2-5 of the variance in amygdala reactivity
- Gene  Amygdala  MDD: Evidence that these genetically
conferred differences in amygdala reactivity mediate some of the
association between the 5-HTTLPR polymorphism and depression
Seminal Example: Amygdala & 5-HTTLPR
- Threat-related amygdala reactivity is correlated with variation in the
serotonin-transporter linked polymorphic region (5-HTTLPR) on the
SLC6A4 gene
- “S allele is bad:” Individuals with the less transcriptionally-efficient
short allele (fewer transporter proteins available to clear serotonin
from the synapse) show heightened threat-related amygdala
reactivity relative to individuals with the long “L” allele
- Gene  Amygdala: Meta-analyses suggest that 5-HTTLPR accounts
for 2-5% of the variance in amygdala reactivity
- Gene  Amygdala  MDD: Evidence that these genetically
conferred differences in amygdala reactivity mediate some of the
association between the 5-HTTLPR polymorphism and depression
Seminal Example: Amygdala & 5-HTTLPR
- Threat-related amygdala reactivity is correlated with variation in the
serotonin-transporter linked polymorphic region (5-HTTLPR) on the
SLC6A4 gene
- “S allele is bad:” Individuals with the less transcriptionally-efficient
short allele (fewer transporter proteins available to clear serotonin
from the synapse) show heightened threat-related amygdala
reactivity relative to individuals with the long “L” allele
- Gene  Amygdala: Meta-analyses suggest that 5-HTTLPR accounts
for 2-5% of the variance in amygdala reactivity
- Gene  Amygdala  MDD: Evidence that these genetically
conferred differences in amygdala reactivity mediate some of the
association between 5-HTTLPR and MDD
The Problem of Assumptions
These data suggest the following etiologic chain:
[GENETIC OBSERVATION] 5-HTTLPR 
[ASSUMPTION] reduced efficacy of 5HTT (protein) 
[ASSUMPTION] too much 5HT in amygdala synapses (chemistry) 
[NEURAL OBSERVATION] increased amygdala reactivity to threat 
*EPIDEM’L OBSERVATION+ MDD, especially among individuals exposed
to stress
The Problem of Assumptions
Kalin (UW)
No relation between polymorphism and amygdalar 5HTT expression
when you actually go in and measure the transporter using PET
“our findings are in agreement with the majority of human PET
studies…that suggest there is not a…detectable relationship between in
vivo 5-HTT binding and s-allele carrier status… our work in the rhesus
monkey, and that of others in humans, calls into question whether this
increased risk is mediated by changes in the expression of the number
of serotonin transporter molecules.”
The Problem of Small Effects
- Common polymorphisms have, at most, weak effects on brain
function and behavior (e.g., 2-5%)
- Small effects are hard to detect and likely to result in nonreplications
(false negatives)
- Prompted the development of large-scale consortiums and datasharing networks…thousands of subjects across dozens of labs
provides the statistical power needed to reliably detect weak effects
- But this also begs the question of so what – why bother if the main
effect of individual genetic polymorphisms is so small
The G*E Strategy
- Ryan and Ahmad argues that examining G*E interactions is more
realistic
- insofar as we believe (e.g., the material covered in prior lectures)
that psychopathology and T&P reflect the interaction of
genetically endowed diatheses and negative life events (e.g.,
stress, adversity, abuse, loss) and learning
- and not the direct consequence or main effect of either G or E
- Ryan argues that the effects are likely to be bigger as well
The Seminal G*E Example
Gene x Stress: 5-HTTLPR S carriers had a strong and positive
relationship between life stress and depression, whereas
L carriers did not
Caspi (Duke)
- Proven VERY contentious (e.g., null meta-analysis in JAMA)
- Generally supported by meta-analyses, especially among studies
that used high quality measures of life stress
- The idea here is to assess the interaction of polymorphisms and life
events on brain structure and function (e.g., 5-HTTLPR x Stress
 amygdala  MDD)
G*E Illustrative Examples
Ryan & Ahmad argue that G*E interactions are likely to play an important role in understanding the influence of
molecular genetics (e.g., 5-HTTLPR) on brain function
But what kinds of effects have the behavioral geneticists discovered (in aggregate)? What kind of
“environmental” factors are we likely to be talking about?
-
Family Conflict Confers Risk: Individuals genetically predisposed to low C/SC were even more impulsive in a
conflictual family environment;
-
Marriage and Religiosity Confer Resilience: Individuals at genetic risk for developing substance abuse were
less likely to develop drinking problems if they were married or religious; Gene*Marriage also found for MDD
-
Low Parental Monitoring and Substance-Abusing Friends Confer Risk: Genetic risk for developing adolescent
substance use and antisocial behavior is exaggerated by these environments
Dick summarizes this by noting that a wide variety of environmental factors can
(a) trigger or
(b) compensate for or regulate the expression of a genetic predisposition
(c) enhance or accentuate a genetic predisposition
G*E Illustrative Examples
Ryan & Ahmad argue that G*E interactions are likely to play an important role in understanding the influence of
molecular genetics (e.g., 5-HTTLPR) on brain function
But what kinds of effects have the behavioral geneticists discovered (in aggregate)? What kind of
“environmental” factors are we likely to be talking about?
-
Family Conflict Enhances Risk: Individuals genetically predisposed to low C/SC were even more impulsive in a
conflictual family environment;
-
Marriage and Religiosity Confer Resilience: Individuals at genetic risk for developing substance abuse were
less likely to develop drinking problems if they were married or religious; Gene*Marriage also found for MDD
-
Low Parental Monitoring and Substance-Abusing Friends Enhance Risk: Genetic risk for developing
adolescent substance use and antisocial behavior is exaggerated by these environments
Dick summarizes this by noting that a wide variety of environmental factors can
(a) trigger or
(b) compensate for or regulate the expression of a genetic predisposition
(c) enhance or accentuate a genetic predisposition
G*E Illustrative Examples
Ryan & Ahmad argue that G*E interactions are likely to play an important role in understanding the influence of
molecular genetics (e.g., 5-HTTLPR) on brain function
But what kinds of effects have the behavioral geneticists discovered (in aggregate)? What kind of
“environmental” factors are we likely to be talking about?
-
Family Conflict Enhances Risk: Individuals genetically predisposed to low C/SC were even more impulsive in a
conflictual family environment;
-
Marriage and Religiosity Confer Resilience: Individuals at genetic risk for developing substance abuse were
less likely to develop drinking problems if they were married or religious; Gene*Marriage also found for MDD
-
Low Parental Monitoring and Substance-Abusing Friends Enhance Risk: Genetic risk for developing
adolescent substance use and antisocial behavior is exaggerated by these environments
Dick summarizes this by noting that a wide variety of environmental factors can
(a) trigger a genetic diathesis (e.g., access to substances, life stress, adversity)
(b) compensate for or regulate the expression of a genetic predisposition (e.g., social norms)
(c) enhance or accentuate a genetic predisposition (e.g., delinquent peers)
In principle, you could adopt a similar approach for molecular genetics (e.g., 5-HTTLPR)
More Sophisticated Approaches:
Gene*Gene & Multilocus Profiles
The phenotype (T&P/Dx) reflects the cumulative effect of all the genes; traits
are massively “polygenic”
In principle, it would be helpful to model gene*gene interactions or develop
more complex additive (many main effects) profiles (high on this, medium on
that, low on the other and so on)
In practice, this is challenging given the combinatorial complexity
Also, profile scores that combine many genes eliminates the possibility of
testing specific mechanistic hypotheses in animal models, back to “black box”
of aggregate heritability
There is considerable excitement about the development of more
sophisticated analytic tools (e.g., machine learning of phenotypically
interesting gene profiles)
More Sophisticated Approaches:
Gene*Gene & Multilocus Profiles
The phenotype (T&P/Dx) reflects the cumulative effect of all the genes; traits
are massively “polygenic”
In principle, it would be helpful to model gene*gene interactions or develop
more complex additive (many main effects) profiles (high on this, medium on
that, low on the other and so on)
In practice, this is challenging given the combinatorial complexity
Also, profile scores that combine many genes eliminates the possibility of
testing specific mechanistic hypotheses in animal models, back to “black box”
of aggregate heritability
There is considerable excitement about the development of more
sophisticated analytic tools (e.g., machine learning of phenotypically
interesting gene profiles)
Neurogenetics Take Homes
1.
There is considerable excitement about the neurogenetics approach.
2.
This reflects both clinical interests (Tx) as well as the basic science hope that it can provide clues about the
molecular differences that influence the effects seen in fMRI studies (e.g., understand influence of 5HT
without actually measuring 5HT).
3.
But assumptions may not be warranted; e.g., 5HTTLPR is unrelated to transporter expression in amygdala
4.
Neurogeneticists face all of the problems outlined by Kendler: The Broken Glass, and, The Jet Mechanic. No
guarantee that there are a limited number of functionally coherent substrates to be identified.
5.
The effects of single polymorphisms, such as 5HTTLPR, tend to be weak, necessitating large, expensive
samples – and begging questions about cost/benefit.
6.
G*E approaches (life stress and 5HTTLPR) have led to much excitement, and may unmask bigger effects and
increased understanding. But at times, it feels like a fishing expedition.
7.
Likewise, G*G interactions (epistasis) and multilocus profiles that address the aggregate effect of many smalleffect genes may prove helpful, but seem to lead back to the black box of aggregate h2 measures.
8.
Combinatorial complexity is daunting (6M variants!). More sophisticated modeling and machine learning
approaches will be needed. The primate brain is too stupid to decipher the human brain without help.
9.
On the assumption that Kendler’s Intermediate Scenarios appear most probable, neurogenetics appears
useful. Especially when it is integrated with mechanistic work in nonhuman models (cf. Borsook; Bogdan)
Brief Aside on How the Environment
Gets Under the Skin
Students:
what’s a plausible mechanism?
How might parenting or exposure to
other risks influence behavior
(phenotype)?
How Does E Get Under the Skin?
Epigenetics provides a biological explanation for how E (parenting, therapy, life events) alters behavior
-
The environment (e.g., learning, stress) can alter gene expression (protein synthesis) without altering the
genome (DNA; hence, not heritable)
-
Gene expression is influenced by transcription factors, which bind to sequences of DNA
-
Binding of transcription factors turns genes on or off
-
Epigenetic mechanisms involve changes to how readily transcription factor can access the DNA
-
E.g., methylation: addition of a methyl group onto a cytosine (1 of the 4 base
pairs that make up DNA) silences the gene because methyl hinders the transcription factors
-
Epigenetic modifications of the genome have long been known to exist e.g., all cells in the body share the
same DNA; accordingly, there must be a mechanism whereby different genes are active in liver cells vs.
neurons
-
Work in rodents by Michael Meaney’s group demonstrates that maternal behavior can influence the adult T&P
of offspring and that this is epigenetic dependent
How Does E Get Under the Skin?
Epigenetics provides a biological explanation for how E (parenting, therapy, life events) alters behavior
-
The environment (e.g., learning, stress) can alter gene expression (protein synthesis) without altering the
genome (DNA; hence, not heritable)
-
Gene expression is influenced by transcription factors, which bind to sequences of DNA
-
Binding of transcription factors turns genes on or off
-
Epigenetic mechanisms involve changes to how readily transcription factor can access the DNA
-
E.g., methylation: addition of a methyl group onto a cytosine (1 of the 4 base
pairs that make up DNA) silences the gene because methyl hinders the transcription factors
-
Epigenetic modifications of the genome have long been known to exist e.g., all cells in the body share the
same DNA; accordingly, there must be a mechanism whereby different genes are active in liver cells vs.
neurons
-
Work in rodents by Michael Meaney’s group demonstrates that maternal behavior (x-fostered) can influence
the adult T&P of offspring and that this is epigenetic dependent
How Does E Get Under the Skin?
Epigenetics provides a biological explanation for how E (parenting, therapy, life events) alters behavior
-
The environment (e.g., learning, stress) can alter gene expression (protein synthesis) without altering the
genome (DNA; hence, not heritable)
-
Gene expression is influenced by transcription factors, which bind to sequences of DNA
-
Binding of transcription factors turns genes on or off
-
Epigenetic mechanisms involve changes to how readily transcription factor can access the DNA
-
E.g., methylation: addition of a methyl group onto a cytosine (1 of the 4 base
pairs that make up DNA) silences the gene because methyl hinders the transcription factors
-
Epigenetic modifications of the genome have long been known to exist e.g., all cells in the body share the
same DNA; accordingly, there must be a mechanism whereby different genes are active in liver cells vs.
neurons
-
Elegant mechanistic work in rodents by Michael Meaney’s group demonstrates that one aspect of the early
environment , maternal behavior (x-fostered), can influence the T&P of offspring and that this is epigenetic
dependent
-
This is exceedingly hard to study in humans because epigenetic mechanisms vary across the brain and body, so
measuring epigenetic effects in blood or saliva may not tell you very much about the amygdala
PSYC 612 R08B:
G-E Correlations:
How Genes Get Outside the Skin
AJ Shackman
9 December 2013
PSYC 612 R08B:
G-E Correlations:
How Genes Get Outside the Skin
Students?
Lemery (ASU)
Jaffee (Penn)
G-E Correlations Defined (Plomin ‘77)
Many sources of influence that we might consider “environmental” are actually non-random and genetic
1. Passive G-E correlation (nature and nurture are confounded)
- among biologically related parents and offspring, the parents provide genotypes AND rearing
environment; thus many parent-child outcome correlations may actually reflect passive G-E effects
-
E.g., the reason children who are spanked or smacked are more aggressive than children who are not
may be that parents and kids share a genetic risk for aggressive behavior (common cause)
2. Evocative G-E correlation
- e.g., a child who is predisposed to having an outgoing, cheerful T&P is more likely to evoke positive
attention from others than a child who is predisposed to N/NE
-
E.g., Individuals with a grumpy, abrasive temperament (N/NE) tend to evoke unpleasant responses
from coworkers and others than cheerful, friendly individuals
3. Active G-E correlation
- Individuals actively select environments
- E.g., individuals predisposed to high E/PE seeking may be more prone to attend parties, go to bars, meet
new people, be exposed to or to try substances of abuse
G-E Correlations Defined (Plomin ‘77)
Many sources of influence that we might consider “environmental” are actually non-random and genetic
1. Passive G-E correlation (nature and nurture are confounded)
- among biologically related parents and offspring, the parents provide genotypes AND rearing
environment; thus many parent-child outcome correlations reflect passive G-E effects
-
E.g., the reason children who are spanked or smacked are more aggressive than children who are not
may be that parents and kids share a genetic risk for aggressive behavior (common cause)
2. Evocative G-E correlation
- e.g., a child who is predisposed to having an outgoing, cheerful T&P is more likely to evoke positive
attention from others than a child who is predisposed to N/NE
-
E.g., Individuals with a grumpy, abrasive temperament (N/NE) tend to evoke unpleasant responses
from coworkers and others than cheerful, friendly individuals
3. Active G-E correlation
- Individuals actively select environments
- E.g., individuals predisposed to high E/PE seeking may be more prone to attend parties, go to bars, meet
new people, be exposed to or to try substances of abuse
G-E Correlations Defined (Plomin ‘77)
Many sources of influence that we might consider “environmental” are actually non-random and genetic
1. Passive G-E correlation (nature and nurture are confounded)
- among biologically related parents and offspring, the parents provide genotypes AND rearing
environment; thus many parent-child outcome correlations reflect passive G-E effects
-
E.g., the reason children who are spanked or smacked are more aggressive than children who are not
may be that parents and kids share a genetic risk for aggressive behavior (common cause)
2. Evocative G-E correlation
- e.g., a child who is predisposed to having an outgoing, cheerful T&P is more likely to evoke positive
attention from others than a child who is predisposed to N/NE
-
E.g., Infant behavioral inhibition evokes parental insensitivity, which then potentiates
maladaptive parent–child interactions over time, exacerbating fear of novelty
3. Active G-E correlation
- Individuals actively select environments
- E.g., individuals predisposed to high E/PE seeking may be more prone to attend parties, go to bars, meet
new people, be exposed to or to try substances of abuse
G-E Correlations Defined (Plomin ‘77)
Many sources of influence that we might consider “environmental” are actually non-random and genetic
1. Passive G-E correlation (nature and nurture are confounded)
- among biologically related parents and offspring, the parents provide genotypes AND rearing
environment; thus many parent-child outcome correlations reflect passive G-E effects
-
E.g., the reason children who are spanked or smacked are more aggressive than children who are not
may be that parents and kids share a genetic risk for aggressive behavior (common cause)
2. Evocative G-E correlation
- e.g., a child who is predisposed to having an outgoing, cheerful T&P is more likely to evoke positive
attention from others than a child who is predisposed to N/NE
-
E.g., Infant behavioral inhibition evokes parental insensitivity, which then potentiates
maladaptive parent–child interactions over time, exacerbating fear of novelty
3. Active G-E correlation (Niche Building)
- Individuals actively select environments
-
E.g., individuals predisposed to high E/PE seeking may be more prone to attend parties, go to bars, meet
new people, be exposed to delinquent peers, and try substances of abuse
Evidence for G-E Correlations
Evidence for G-E Correlations
Mostly from FTA studies demonstrating that “environmental” measures are heritable, including many linked to
psychopathology
e.g., marital quality, social support, parental discipline/warmth, family environment, peer relationships,
negative life events such as divorce and exposure to trauma
Environments are heritable because genotype influences behaviors that evoke, select, and modify features of
the environment
- Environments less amenable to behavioral modification are less heritable, e.g., the death of a loved
one, losing one’s home in a natural disaster
- Than those that depend on the individual’s behavior, e.g., divorce, getting fired
Take home: Genetic risk factors do not necessarily have direct effects on phenotypes (T&P, Dx), but can work
indirectly by modifying sensitivity to environmental risk factors (active G-E) or by influencing exposure
to risk (passive, evocative G-E)
Evidence for G-E Correlations
Mostly from FTA studies demonstrating that “environmental” measures are heritable, including many linked to
psychopathology
e.g., marital quality, social support, parental discipline/warmth, family environment, peer relationships,
negative life events such as divorce and exposure to trauma
Environments are heritable because genotype influences behaviors that evoke, select, and modify features of
the environment
- Environments less amenable to behavioral modification are less heritable, e.g., the death of a loved
one, losing one’s home in a natural disaster
- Than those that depend on the individual’s behavior, e.g., divorce, getting fired
Take home: Genetic risk factors do not necessarily have direct effects on phenotypes (T&P, Dx), but can work
indirectly by modifying sensitivity to environmental risk factors (active G-E) or by influencing exposure
to risk (passive, evocative G-E)
G-E Correlation Take Homes
3 Kinds of G-E Correlations: Passive, Evocative, and Active
Take home: Genetic risk factors do not necessarily have direct effects
on phenotypes (T&P, Dx), but can work indirectly by modifying
exposure to environmental risks (e.g., stress, substances, delinquent
peers) that reinforce particular personality traits or precipitate frank
psychopathology
More fundamentally, these data emphasize that Nature/Genotype and
Nurture/Environment are not mutually exclusive forces, but often work
together to increase or decrease the likelihood of important outcomes
Stop Here;
Switch to Recap PPT
Long Term Prospects, The Ugly
There are many many ways to make a neuron hypofunction (shrunken
dendrites, too few or dysfunctional receptors, downregulated 2nd
messenger systems, or deficient transport mechanisms.
There are even more pathways to make a complex
circuit dysfunction
This scenario is likely if there are hundreds of distinct biochemical
changes that individually contribute to Dx (neither necessary nor
sufficient) with independent pathways to the phenotype.
Perhaps there are too many ways for the human brain to produce symptoms/signs of
psychiatric disorders (for example, sad mood, auditory hallucinations, grandiosity) for a limited
number of biologically coherent pathways to emerge from the 100’s or 1000’s of genes that
make small contributions to risk.
Here, psychiatric disorders (or T&P) arise at such a high level within the mind–brain system that
we have no way to integrate GWAS or sequencing findings.
If so, then a genetic mess is a plausible outcome and genes are the ‘wrong level’ for trying to
understand the biological mechanisms that cause such a trait.
Long Term Prospects, The Good
We could get lucky 
In the most optimistic scenario, nearly all of the verified risk genes identified through GWAS or
sequencing will map to a single coherent inter-connected biological pathway.
This will occur only if the genetic underpinnings of the disorder reflect a high degree of
etiological homogeneity. i.e. a single disease process (“equifinality”)
Intermediate scenarios (neither Ugly nor Good) are possible
Strategy for Linking FTA to Molecules
Dick notes that it is useful to first search for G*E interactions in FTA studies
There are a huge number of environmental factors that could potentially be assessed
Useful to build off the already well-developed developmental literature
In cases where there is an interaction between Genes (in aggregate) and Environment (e.g., peer delinquency
exposure), that is, “a hit” in the FTA literature
It makes sense to drill down into specific genes, either candidate variants or GWAS
The Broad Goal
Kendler underscored our ignorance about the biology linking genotypes to phenotypes.
Developing a mechanistic understanding of the neurobiology of T&P and their associated psychiatric
disorders would allow us to:
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Redefine diagnostic categories and T&P traits in terms of quantifiable etiology (root causes)
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Develop novel treatments or prevention efforts targeting links in the etiological chain
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Identify at-risk individuals early (e.g., carriers of a particular polymorphism)
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Predict treatment response (e.g., carriers of a particular polymorphism)
-
Monitor treatment in terms of changes in the underlying neural systems
Translational Promise
Sara argues that, in principle, if one could identify with high sensitivity and specificity at-risk G-E pairs
- At-risk kids paired with risky environments (parental style, peers, adversity, abuse, etc.)
You could target them for precision interventions BEFORE the onset of cumulative damage
- in effect, she argues for a more nuanced extension of the Moffitt PNAS strategy
- instead of identifying kids with low C/SC
- identify kids with low C/SC and other “environmental” risk factors
- this is akin, as I understand it, to what Andrea’s lab does (ADHD kid + parent with sub-optimal skill)
- potentially, one could use biomarkers (gene screens) to identify high-risk parent-kid dyads
Some Success with GWAS
- GWAS: Genome wide association study
- brute force approach—testing one-by one the correlation between
traits and hundreds of thousands of common genetic variants
- the opposite of ‘candidate gene’ studies that utilize theories to test a
small number of genetic variants
- GWAS treats every common genomic variant the same, allowing
detection of pathogenic variants never previously conceived of
- Penalty is low power, due to correction for multiple comparisons
- Trade off is beginning to pay off.
Some Success with GWAS
Very recent GWAS’s have identified sets of polymorphisms that
collectively account for much of the heritability of major psychiatric
disorders
e.g., 32% variation in MDD (phenotype) can be explained by
individual polymorphisms (genes)
- Suggests that a substantial proportion of genetic variation results
from very large numbers of small effect variants
- However, like FTA studies, these GWAS results yield no insight into
biological intermediaries. They only tell us that, somewhere on the
genome, variants exist, which impact disease risk
R08A/B Key Learning Objectives
1. Recap: What % of the variance in T&P (phenotype) is due to genes/nature vs.
environment/nurture?
2. What is heritability (h2)? What are the limitation of this parameter? What are common
misconceptions about h2?
3. What has psychiatric genetics taught us?
4. What are the long-term prospects for linking heritable traits (e.g., T&P) to distinct
neurobiological systems?
5. There is a considerable excitement about so-called neurogenetic approaches that
combine measures of molecular genetic variation (SNPs) with measures of brain function
(fMRI). What are the seminal observations? What are some of the key challenges facing
the nascent field of neurogenetics?
6. What are G*E interactions? How does genetic influence depends on the environment?
7. How does the environment get under the skin?
8. What are the 3 kinds of G-E correlations? What is the fundamental implication of G*E
interaction and G-E correlations for the Nature vs. Nurture dichotomy