Shackman Psyc210 Module10 NatureNurture Part1

If everything is heritable, what is heritability really
teaching us?
Moderntechnologies have provoked intense disagreement
between scientists who envision a future in which biogenetic
theories will enrich or even replace psychological theories, and
others who consider biogenetic theories exaggerated,
dehumanizing, and dangerous.
Both sides of the debate about the role of genes and brains in the
genesis of human behavior have missed an important point: All
human behavior that varies among individuals is partially
heritable and correlated with measurable aspects of brains,
but the very ubiquity of these findings makes them a poor basis for
reformulating scientists' conceptions of human behavior.
Turkheimer Psychol Review 1998
Nuts & Bolts Plan for Today
Nuts & Bolts Plan for Today

Lecture on heritability (Visscher)
Take-home critical thinking
questions
PSYC 210:
The nature & nurture of T&P, Part 1
AJ Shackman
12 March 2015
Conceptual Roadmap for

Today

Today
What is heritability?

Today
What is heritability? Students whats
your intuition?

Today
Temperament is often conceptualized
as biological and inherited.
e.g., The Malfoys
But just how heritable is T&P? Does it

breed true?
Students?

Today
Temperament is often conceptualized
as biological and inherited.
e.g., The Malfoys
But just how heritable is T&P? Does it

breed true?

Today
We have been trained (brain-washed?)
by our culture to think in terms of
heritability.
To blame a family or a races 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?

Today
We have been trained (brainwashed?) by our culture to think in
terms of heritability.
To blame a family or a races genes.
But what are the limitations of
heritability measures?
Four essential lessons about

the nature & nurture of T&P
Lesson 1
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!
Lesson 1
2014
biological destiny!
Lesson 1
2014
biological destiny!
Recently, Kandler (2012) provided a more formal synthesis

of previous findings on age trends in heritability levels of the
two broad trait domains of neuroticism and extraversion.
Covering studies on age groups from childhood to old age, this
meta-analytic review revealed decreases in heritability
estimates of neuroticism throughout the entire adult life span
(from h2 = 0.45 at age 20 years to h2 = 0.20 at age 80 years).
The heritability of extraversion, on the other hand, slightly
increased until age 30 years but decreased continuously
thereafter
(from h2=0.50 to h2 = 0.35 at age 80 years).
Larger Implication
Larger Implication
Genes (or their absence) do not hard-wire
people for certain behaviors. There is no gene
for understanding calculus [or extraversion or
neuroticism or self-control]
Specific behaviors are [not biologically] hardwired. M.I.T. math majors arent born doing
.Its not just genes make brain make
behavior. You have environment and
experience too.
Dobbs NY Times 2007; Miller PPS 20
Larger Implication
Genes (or their absence) do not hard-wire
people for certain behaviors. There is no gene
for understanding calculus [or extraversion or
neuroticism or self-control]
Specific behaviors are [not biologically] hardwired. M.I.T. math majors arent born doing
calculus.Its not just genes make brain
make behavior. You have environment and
experience too.
Dobbs NY Times 2007; Miller PPS 20
Lesson 2
Genes (nature) can influence
environments (nurture)
Draco Malfoys Genes

(DNA)
Draco Malfoy, Across Early Development
Students What exactly is Dracos environment ? What are

some likely key elements?
Lesson 2
Draco Malfoys Genes

(DNA)
Lesson 2
Draco Malfoys Genes

Draco Malfoys (Partially Inherited) Environment
(DNA)
Lesson 2
Draco Malfoys Genes

Draco Malfoys (Partially Inherited) Environment
(DNA)
Students What exactly constitutes Dracos environment ?
Key elements?
Lesson 2
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
Lesson 2
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
Stress of disintegrating relations / divorce can reinforce N/NE
Lesson 3
Remember, when a measure of the
environment and T&P are
correlated, 2 causal pathways are
possible
T&P Environment
e.g., childs T&P evokes a style of nurturing
-orEnvironment T&P
Lesson 3
possible
T&P Environment
-orEnvironment T&P
Lesson 3
possible
T&P Environment
-orEnvironment T&P
Lesson 4
Nature is not static
Lesson 4
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
Lesson 4
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?
e [modern] concept of heritabilitywas introducednearly a century ag

pite continuous misunderstandings and controversiesheritability rema
to the prediction of disease risk in medicine
What is heritability (h2)
https://en.wikipedia.org/wiki/Heritabil

A single number indicating the % of variation
between individuals in a population due to
genotype (pedigree); 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

Total Trait Variance (TTV) = Genotypic
Heritability = GV / PV = fraction of total

Total Trait Variance (TTV) = Genotypic
Heritability = GV / TTV = fraction of total
How well can you predict Ginnys hair color

knowing that she is related to other members of
the Weasley clan?
Whadya mean the % of variance in the phenotype (e.g. height)

predicted by the biological pedigree
How is h2 estimated??
Estimating heritability (h2)

Family members differ in their degree of genetic relatedness
You can harness this to estimate heritability
For example, h2 can be estimated using the correlation
between parent (mean of Mom and Dad) and offspring
phenotypes
Other approaches include the correlation between full
siblings or the difference in the correlation of identical (MZ)
and fraternal (DZ) twins

phenotypes

phenotypes

phenotypes

phenotypes
Heritability (h2) estimates can

mislead
If non-trivial, ignoring G*E interactions
deflates h2 (e.g., MDD is not very
heritable)
Details are not important

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 MEs)
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)

mislead
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 MEs)
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)

mislead
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

MEs)
the effect of the genotype depends upon 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)

mislead
cattle fed in accord with milk production

MEs)
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)

mislead
H2 usually ignores G-E correlations (focusing on additive
MEs)
cattle fed in accord with milk production)

MEs)
Ignoring G-E correlations inflates h2 (IQ is really, really

heritable)
Ignoring G*E interactions deflates h2 (MDD is not very
heritable)

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
Huang et al PNAS 2012

mislead
Growing evidence that the impact of
particular variants is highly dependent on
genetic context
Effects depend upon what other genes are
doing

mislead
Growing These
effects bias
in
evidence
thatheritability
the impact
of
different ways depending on how
particularheritability
variants
is highly
on
was estimated
and dependent
the
specifics of the effect
genetic context
HH Goldsmith
Effects depend upon
what other genes are
Bottom
line:
Heritability
is
doing
complex and estimates often
entail simplifying
that may be wrong
assumptions
Heritability (h2) is not absolute

Ratio (GV/TTV) 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
No variation
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

Ratio (GV/TTV)): Made larger by diversifying the genetic
variance &/or minimizing environmental effects
constraint
e.g.,
in disinhibition (partying, drinking, and
No Differences
TV

Ratio (GV/TTV): Made larger by diversifying the genetic
constraint
e.g.,
Differences
in disinhibition (partying, drinking, and
Increased
TV

Ratio (GV/TTV): Made larger by diversifying the phenotypic
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., if EVERYONE smokes or if NO ONE smokes,

then smoking
will
not be
a heritable phenotypic trait
Sample specific,
as with
other
correlations




then smoking
will
not be
Sample specific,
as with
other
correlations




then smoking
will
not be
Sample specific,
as with
other
correlations


in a conservative religious environment (Amish)

e.g., if EVERYONE smokes or if NO ONE smokes (no variance),
then smoking will not be a heritable phenotypic trait


in a conservative religious environment (Amish)
became more socially acceptable (no change in men)
4 common misconceptions
#1
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
Students Why is this
passed on no!
wrong?
Genes are passed on, not
phenotypes/traits
#1
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
#2
40% of Alexs T&P is inherited
(nature) and 60% is environmental
(nurture). Wrong!
h2 reflects the proportion of variation
Students Why
is this
between individuals
(Alex
vs. Jee vs.
wrong?
Hannah) in a population that is influenced
by genetic factors.
h2 describes the population variation, not
individuals (Alex) within that population
#2
40% of Alexs 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
#3
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 your
destiny. You, like your father, are
now mine.
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
#3
destiny. Wrong!
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
the phenotype
ife alter
Example:
percent
heritability
estimate
is pretty
wild, said
Dr. Krasne
E.g., 80%
of the variation
in height
is heritable,
yet people
d that if it was true, it shouldn't matter too much what you
around the world have grown much taller in the face of
you go to school. Everything would fall into place.
improved nutrition and medical care
NY Times, 12 October 199
#3
destiny. Wrong!
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)
Heritability describes what is; it does not predict what could
be. Krapohl et al PNAS 2004
#3
destiny. Wrong!
and medical care)
#3
destiny. Wrong!
and medical care)
#3
destiny. Wrong!
and medical care)
#3
High heritability implies genetic determination or destiny.
Wrong!
Does not mean that the mean phenotype is fixed, because the
environment can markedly alter the mean phenotype
because of changes in the environment (improved nutrition and
medical care)
Heritability describes what is; it does not predict what
could be.
Krapohl et al
PNAS 2004
#3
Wrong!
Furthermore, humans have free will in the face of apparent
genetic destiny
Alcoholism, smoking, and breast cancer are all heritable
We have the choice to refrain from drinking, to not smoke, and even
to have a masectomy
X
Xx
x
X
x
Kendler Mol Psych 2013
#3
Wrong!
genetic destiny
But we have the choice to refrain from drinking, to not smoke, and
even to have a prophylatic mastectomy, even if it runs in our family
X
Xx
x
X
x
#3
Wrong!
genetic destiny
even to have a prophylatic mastectomy
Xx
x
X
x
#3
Wrong!
genetic destiny
even to have a prophylatic mastectomy
Like Luke and Angelina,
we can proactively
address the problems
that run in our families
X
x
What Does 80% Heritable Even

Mean?
High heritability implies genetic
determination or destiny. Wrong!
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
High heritability implies genetic
determination or destiny. Wrong!
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
Heritability is informative about the nature, origins, or
plasticity 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
plasticity 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
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
interventions
#4
Heritability is informative about the nature, origins, or plasticity of
mean differences across groups or time. Wrong!
Heritability is not informative about mean differences across groups (e.g.,
races) or time (e.g., birth cohorts)
E.g., height and IQ are highly heritable, but they are not fixed
2000: US white men were taller than ever before but are now about ~5 c
shorter than Dutch men. Go Orange!
This reflects changes in the environment (nutrition, healthcare)
interventions
#4
plasticity of mean differences across groups or time.
Wrong!
Example 1: USA vs The Netherlands
1850: US white men were ~9 cm taller than Dutch males.
USA! USA! USA!
2000: 150 yrs later, US white men were taller than ever
before but are now about ~5 cm shorter than Dutch men.
Go Orange!
#4
Wrong!
USA! USA! USA!
Go Orange!
#4
Wrong!
USA! USA! USA!
Go Orange!
#4
Wrong!
Example 2: N vs. S Korea
1930: Individuals from the northern and southern parts of
the Korean peninsula were of equal height
2000: Following 70 years of dictatorial mis-rule, men in N
Korea are now about 6 shorter than their genetically
similar counterparts in S Korea
#4
Wrong!
similar counterparts in S Korea
#4
Wrong!
identical relatives in S Korea
#4
Wrong!
These examples reflect differences in the environment

(stress, nutrition, healthcare)
Take home: High heritability should not deter the
development of interventions and tells us little or nothing
about the biological origins or mutability of group (e.g.,
race) differences in a phenotype
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

heritable

SES, toxin exposure, dictators) are important for
etiology
etiology

heritable

SES, toxin exposure, dictators) are important for
etiology
etiology
- But FTA studies are correlational; no insight into
- Kendler notes that because diagnoses (like T&P
traits) are artificial categories that do not carve
nature at the joints, simply showing heritability
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)
To be continued next
time
1.
Some Take Homes on

Nature/Nurture
T&P traits (~45%) and psychiatric disorders are heritable
2.
Genes are passed down, not phenotypes. Heritability refers to the % of betweenindividual 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. Kendlers 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.
1.
Some Take Homes on

Nature/Nurture
2.
3.

FTA studies
1.
Some Take Homes on

Nature/Nurture
2.
3.

FTA studies
1.
Some Take Homes on

Nature/Nurture
2.
3.

FTA studies
1.
Some Take Homes on

Nature/Nurture
2.
3.

7. Switching from heterogeneous, trait-like superfactors and Dxs to simpler
endophenotypes may prove helpful.
1.
Some Take Homes on

Nature/Nurture
2.
3.

6. Switching from heterogeneous, trait-like superfactors and Dxs to simpler
intermediate phenotypes may prove helpful.
Critical Thinking Questions

Please select 2 of the options

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 or in the assigned
paper on free will by Kendler change how you think
about this?
(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC366389
1)
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.

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 or in the assigned
paper on free will by Kendler change how you think
about this?
(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC366389
1)
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.

1.
2.
X
X
3. Over the past century, behavioral geneticists have convincingly

demonstrated that
Virtually every imaginable kind of behavior is [significantly]...
heritable Once we accept that basically everythingnot only
schizophrenia and intelligence [and T&P], but also marital status and
television watching [and voting behavior]is heritable, it becomes
clear that specific estimates of heritability are not very important.
Johnson et al Curr Directions Psychol Sci 2010
(see also Turkheimer Psychol Review 1998)
What do you think?
What are the implications of the omnipresence of genetic effects for
your understanding of the world around you? If everything is
somewhat genetically determined (and few things are completely
determined), how does it change how you think about intervention
or morality (e.g. if BMI/obesity is heritable, should I diet? If anti-social
behavior is heritable, should I press for prisons over rehab

1.
2.
X
X

demonstrated that
What do you think?
somewhat genetically determined (and few things are completely
determined), how does it change how you think about intervention
or morality (e.g. if BMI/obesity is heritable, should I diet? If anti-social
behavior is heritable, should I press for prisons over rehab

1.
2.
X
X

demonstrated that
What do you think?
somewhat biological and genetically determined (and few things
are completely determined), how does it change how you think
about intervention or morality (e.g. if BMI/obesity is heritable, should
I diet? If anti-social behavior is heritable, should I press for prisons
Time Permitting
Optional Review Questions
Kagans model of BI
A. Shows a number of
parallels with N/NE and
Grays BIS, reinforcing the
idea that childhood
temperament and adult
personality are closely
related
B. Shows a number of
important differences from
N/NE and Grays BIS,
reinforcing the idea that
childhood temperament
and adult personality are
distinct kinds
Children with elevated behavioral

inhibition (BI)
A. Are more likely to develop anxiety,
mood, and co-morbid substance
abuse disorders later in life
B. Are more likely to develop
psychopathology if they show
stable, high levels of BI across
development
C. Are shy and reticent in the face of
novelty and potential threat (e.g.,
scary robot, human intruder)
D. May show elevated levels of the
stress hormone cortisol
E. Show a R > L pattern of frontal EEG
F. Show heightened amygdala
reactivity to novel faces in
adulthood
G. All of the above
Which is true
A. Hannah is a 6
y.o. boy
B. Micah is an 18
m.o. girl
C. Both of Dr. Ss
kids are cute as
all get out
D. All of the above
Anxiety disorders, such as GAD, and

major depression are
A. Categorically different
B. Often co-morbid and
show a number of
other similarities, in
terms of therapeutic
response, heritability,
and do on, suggesting
that they are closely
related to one another
and form a spectrum
Treatments targeting anxiety

disorders
A. Tend to influence
N/NE as well as
depression
B. Selectively
influence the
targeted disorder
C. Only help some
patients
D. A and C
E. B and C
Anxiety disorders, depression, and

N/NE appear to share
A. Genes
B. Neural
substrates (e.g.,
amygdala
hyper-reactivity)
C. Both
Lesion studies in rodents, monkeys, and

humans demonstrate that the amygdala
A. Is required for the
normal acquisition
of new fear learning
(conditioned
emotional
response)
B. Not required
C. Is required for the
retention of already
learned fears
Elevated N/NE
A. Is common
among anxiety
patients
B. Is common
among
depression
patients
C. Both
Psychological pathogens, such as

stress and family conflict
A. Exert similar
effects on
depression, anxiety
disorders, and
N/NE, suggesting a
common substrate
B. Have distinct
effects on T&P vs.
depression vs.
anxiety disorders
Amygdala lesions in
monkeys block
A. The acquisition
of new
conditioned
fears
B. Innate anxiety
about snakes
C. Both
Jerry Kagan argues that the root cause

of childhood behavioral inhibition (BI) is
A. An over-reactive
amygdala
B. Maladaptive
cognitive coping
mechanisms
C. Worry
D. Disress
E. Social reticence
F. Shyness
The administration of a benzodiazepine

(anti-anxiety medication)
A. Causes a dosedependent
reduction in
amygdala
activation
B. Causes a dosedependent
increase in
amygdala
activation
Why do some individuals develop particular

disorders, such as specific phobia of dogs?
A. Learning and experience
B. Core vulnerability
(heightened
neuroticism, hyperreactive amygdala,
inadequate regulation of
the amygdala)
C. Both, neither is
sufficient to explain the
development of specific
emotional disorders
The RoboGator Experiment: Amygdala

lesions in rodents attenuate
A. Reticence to get the food
pellet in the presence of
the remote-control
robogator, suggesting a
substrate for the reticence
demonstrated by BI kids,
consistent with lesioned
monkeys and the human
intruder
B. The amount of time hiding
in the nest area (outside
the arena containing the
Rgator)
C. All of the above
Amygdala damage
A. Increases ratings
of trust and
approachability to
faces that are
normally deemed
untrustworthy
B. Has no
consequence of
social interactions
or social cognition
N/NE is
A. A specific risk
factor for
anxiety
disorders
B. A nonspecific
risk factor for a
broad range of
psychiatric
disease
Patient SM has circumscribed bilateral

destruction of her amygdalae. She
A. Picks up snakes and
spiders, despite
professing anxiety
B. Shows no fear in the
haunted house
C. Is unable to acquire
new conditioned fears
in the lab
D. Quickly returned to
the park where she
was assaulted
Is BI a viable intermediate phenotype

for social anxiety disorder
A. Yes
B. No
Emotional disorders and

N/NE
A. Are
fundamentally
different
B. Reflect a
common cause
C. Are
categorically
distinct
The End
Material to Consider Adding

for Next Semester
This would be awesome to include

but would take some work
First, GE Correlation
Text, pages 318-325
3 types of G-E correlation are
generally recognized
Genotype-Environment
Correlation
Passive - arises because

parents provide both the
genes and the environment of
their children
Correlation
Evocative (Reactive) arises because an
individuals social
environment is partially a
function of how others (not
necessarily family) react to
his/her behavior
Correlation
vs.
Active - arises because an individuals

environment is partially a function of
his/her choices. Is this really a main
effect of G?
vs.
Why is G-E Correlation

Important?
Familial resemblance in intact nuclear

families that is attributed to genetic or
environmental factors might be due to
passive G-E correlation
Heritable contributions on behavioral
outcomes might be due in part to reactive
and active G-E correlation effects
G-E correlation effects may contribute to
the developmental stability of behavior
G-E correlation and its changing nature as
children age is the basis for a theory of
development (next slide)
Goldsmith Slides on Genetics,

Eugenics, and Discrimination
Genetic Determinism &

Genetic Discrimination
The problem may be more
widespread than realized.
Belief in genetic determinism is a
root cause of genetic
discrimination.
Nature of Genetic
Influence: what have we
learned?
Heritability:
Most human behavioral traits are in

part heritable
Heritability estimates are
approximations
Heritability is not an index of
(non)malleability
Consistent with other topics

from the course
Quote from prominent science

administrator
A 70 percent heritability estimate is
pretty wild, said Dr. Norman Krasnegor,
chief of the Human Learning and Behavior
Branch of the National Institute of Child
Health and Human Development. He said
that if it was true, it shouldn't matter
too much what you do or where you
go to school. Everything would fall
into place.''
NY Times, 12 October 1990
A principled critique
of Behavior Genetics
For psychologists, as well as for medical
researchers, the purpose of identifying
undesirable predispositions of individuals
should be to devise more effective healthpromoting interventions, not to discourage
such attempts on the supposition that
these predispositions are genetically
based and therefore intractable.
D. Baumrind (1993)
I think it wont be too

many years before
parents will be able to
go home from the
hospital with their
newborn babies with
a genetic map in their
hands that will tell
them, heres what
your childs future
will be like.
I think it wont be too many

years before parents will be
able to go home from the
hospital with their newborn
babies with a genetic map
in their hands that will tell
them, heres what your
childs future will be
like.
-- William J. Clinton
Remarks in Knoxville,
Tennessee
October 10th, 1996
http://www.presidency.ucsb.edu/ws/index.php?pid=52079
Eugenics (WellBorn)
if talented men were mated with
talented women, of the same mental and
physical characters as themselves,
generation after generation, we might
produce a highly-bred human race, with
no more tendency to revert to meaner
ancestral types than is shown by our
long-established breeds of race-horses
and fox-hounds.
Galton (1865; p. 319)
Some day we will realize that

the prime duty, the
inescapable duty, of a good
citizen of the right type is
to leave his or her blood
behind him in the world.
Theodore Roosevelt
Birth control itself, often

denounced as a violation of
natural law, is nothing more or
less than the facilitation of the
process of weeding out the
unfit, of preventing the birth
of defectives or of those who
will become defectives.
If people are fit to live, let them live

under decent human conditions. If
they are not fit to live, kill them
in a decent human way.
GBS (1934)
the better stocks have
not been replacing their
numbers, while the stupider
and less healthy have been.
W.B. Yeats
I feel that the source from

which the stream of madness is
fed should be cut off and
sealed up before another year
has passed, W. Churchill
(1910)
Demise of the Eugenics

Movement
Association with Nazi movement
Nuffeld Bioethics Council (2002):
part of the reason for the decline
in the support of eugenic policies in
many countries from the 1930s onward
was scientific research which
demonstrated that the policies of
segregation and sterilisation of
those deemed to be unfit would not
achieve their stated goals.
In 1971, the incoming president of the American

Association for the Advancement of Science cheerfully
announced "the right of every child to be born with a
sound physical and mental constitution, based on a
sound genotype." Where rights exist, responsibilities
cannot trail too far behind. Bentley Glass continued: "No
parents will in that future time have a right to burden
society with a malformed or a mentally incompetent
child."
Is Eugenics
Dead?
Down Syndrome: The Denmark

Experience
Number of Down Syndrome
In 2000, ~50% of
DS cases were
identified
prenatally
2004 Prenatal
Screening
Guidelines
Pregnant women
offered risk
assessment for DS
> 80% of at-risk
hadC. CVS
Ekelund,
K., et al. (2008). Impact of a new national
screening policy for Down's syndrome in Denmark: Population
> 90% of DS cases
based cohort study. British Medical Journal, 337, 7.
detected prenatally
RECENT England and Wales

Despite the number of births in 1989/90 being
similar to that in 2007/8, antenatal and postnatal
diagnoses of Down's syndrome increased by 71%
(from 1075 in 1989/90 to 1843 in 2007/8).
However, numbers of live births with Down's
syndrome fell by 1% (752 to 743; 1.10 to 1.08
per 1000 births) because of antenatal screening
and subsequent terminations. In the absence of
such screening, numbers of live births with
Down's syndrome would have increased by 48%
(from 959 to 1422), since couples are starting
families at an older age. Among mothers aged
37 years and older, a consistent 70% of affected
pregnancies were diagnosed antenatally. In
younger mothers, the proportions of pregnancies
diagnosed antenatally increased from 3% to 43%
What is the most

discriminated against
genetically
determined condition
in the world today?
prenatal
screening
rearing to
adulthood
95% of pregnancies that

screen positive are
terminated
NEW YORK, SUNDAY, APRIL 22, 2001
outlawed in 1994
most common
among educated
women
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

- its 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
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

- its 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
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 & 5HTTLPR
- 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


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


relative to individuals with the long L allele
- Gene Amygdala: Meta-analyses suggest that 5HTTLPR accounts for 2-5% of the variance in amygdala
reactivity


relative to individuals with the long L allele
- Gene Amygdala: Meta-analyses suggest that 5HTTLPR accounts for 2-5% of the variance in amygdala
reactivity
reactivity mediate some of the association between 5-
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
[EPIDEML OBSERVATION] MDD, especially among
individuals exposed to stress
he 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 studiesthat 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
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 data-sharing networksthousands 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
e Seminal G*E Example
Gene x Stress: 5-HTTLPR S carriers had a strong

and positive relationship between life stress and
depression, whereas
Caspi (Duke)
L carriers did not
- 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

function
about?
-
Family Conflict Enhances Risk: Individuals genetically predisposed to low C/SC were

Low Parental Monitoring and Substance-Abusing Friends Enhance Risk: Genetic

these environments
(a) trigger or
(b) compensate for or regulate the expression of a genetic predisposition
(c) enhance or accentuate a genetic predisposition

function
about?
-
Family Conflict Enhances Risk: Individuals genetically predisposed to low C/SC were

Low Parental Monitoring and Substance-Abusing Friends Enhance Risk: Genetic

these environments
(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)
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
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
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 small-effect 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.
Brief Aside on How the Environment

Gets Under the Skin
Students:
whats 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 Meaneys group demonstrates that maternal behavior can
influence the adult T&P of offspring and that this is epigenetic dependent

-
the DNA
-
Work in rodents by Michael Meaneys group demonstrates that maternal behavior (xfostered) can influence the adult T&P of offspring and that this is epigenetic dependent

-
the DNA
-
Elegant mechanistic work in rodents by Michael Meaneys 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
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

77)

AND rearing environment; thus many parent-child outcome correlations reflect
passive G-E effects
-

E.g., Individuals with a grumpy, abrasive temperament (N/NE) tend to evoke
unpleasant responses
from coworkers and others than cheerful, friendly individuals
-


77)

passive G-E effects
-

-
E.g., Infant behavioral inhibition evokes parental insensitivity, which then

potentiates
maladaptive parentchild interactions over time, exacerbating fear of novelty


77)

passive G-E effects
-

-
E.g., Infant behavioral inhibition evokes parental insensitivity, which then

potentiates
maladaptive parentchild interactions over time, exacerbating fear of novelty
3. Active G-E correlation (Niche Building)

-
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
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 ones home in a natural disaster
- Than those that depend on the individuals 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 GE) or by influencing exposure
to risk (passive, evocative G-E)

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 ones home in a natural disaster
- Than those that depend on the individuals 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 GE) 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 2 nd
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 100s or 1000s of genes that make small
contributions to risk.
Here, psychiatric disorders (or T&P) arise at such a high level within the
mindbrain system that we have no way to integrate GWAS or sequencing
findings.
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:
-
Redefine diagnostic categories and T&P traits in terms of quantifiable etiology (root
causes)
Develop novel treatments or prevention efforts targeting links in the etiological

chain
Identify at-risk individuals early (e.g., carriers of a particular polymorphism)
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 Andreas 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 approachtesting 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 GWASs 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?
Kendlers 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 1000s 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)

heritable

etiology
heritability of The Disorder does not imply a

heritable

etiology
heritability of The Disorder or The Trait does not

heritable

etiology
- Kendler notes that because diagnoses (like T&P
traits) are artificial categories that do not carve
nature at the joints
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

Imagine that one key mindbrain circuit (for example, the grief system) is
like a glass.
The total strength of the glassthe resilience of the systemreflects 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).

Imagine that one key mindbrain circuit (for example, the grief system) is
like a glass.
The total strength of the glassthe resilience of the systemreflects 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).

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.

Good Scenario:
This would occur if, in all humans, the glass developed with one deep notch
in itone 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 notchthe weak link in
the system.

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
Kendlers 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

the human genome.
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.

the human genome.
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 airplanethe functioning of
the wing flaps. The flap fixers (Big Pharma) are ecstatic.

the human genome.
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 airplanethe 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 parts3 to 5 parts eachthat reflect individual
sub-systems. But most of the parts seem random and cannot be

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If everything is heritable, what is heritability really

Nuts & Bolts Plan for Today

Nuts & Bolts Plan for Today

Conceptual Roadmap for

Conceptual Roadmap for

Conceptual Roadmap for

Conceptual Roadmap for

But just how heritable is T&P? Does it

Conceptual Roadmap for

But just how heritable is T&P? Does it

Conceptual Roadmap for

Conceptual Roadmap for

Four essential lessons about

Recently, Kandler (2012) provided a more formal synthesis

Dobbs NY Times 2007; Miller PPS 20

Dobbs NY Times 2007; Miller PPS 20

Draco Malfoys Genes

Draco Malfoy, Across Early Development

Students What exactly is Dracos environment ? What are

Draco Malfoys Genes

Draco Malfoys Genes

Draco Malfoys Genes

e [modern] concept of heritabilitywas introducednearly a century ag

What is heritability (h2)

What is heritability (h2)

What is heritability (h2)

What is heritability (h2)

How well can you predict Ginnys hair color

Whadya mean the % of variance in the phenotype (e.g. height)

Estimating heritability (h2)

Estimating heritability (h2)

Estimating heritability (h2)

Estimating heritability (h2)

Estimating heritability (h2)

Heritability (h2) estimates can

Heritability (h2) estimates can

H2 usually ignores G*E interactions (focusing on

If non-trivial, ignoring G-E correlations inflates h2 (e.g., IQ

Heritability (h2) estimates can

H2 usually ignores G*E interactions (focusing on

If non-trivial, ignoring G-E correlations inflates h2 (e.g., IQ

Heritability (h2) estimates can

H2 usually ignores G*E interactions (focusing on additive

If non-trivial, ignoring G-E correlations inflates h2 (e.g., IQ is

Heritability (h2) estimates can

H2 usually ignores G*E interactions (focusing on additive

If non-trivial, ignoring G-E correlations inflates h2 (e.g., IQ is

Heritability (h2) estimates can

H2 usually ignores G*E interactions (focusing on additive

Ignoring G-E correlations inflates h2 (IQ is really, really

Heritability (h2) estimates can

Huang et al PNAS 2012

Heritability (h2) estimates can

Huang et al PNAS 2012

Heritability (h2) estimates can

Huang et al PNAS 2012

Heritability (h2) is not absolute

Heritability (h2) is not absolute

Heritability (h2) is not absolute

Heritability (h2) is not absolute

Heritability (h2) is not absolute

e.g., Differences in disinhibition (partying, drinking, and

Heritability (h2) is not absolute

e.g., if EVERYONE smokes or if NO ONE smokes,