Shackman Psyc210 Module10 NatureNurture Part1 031215

If
everything is heritable, what is heritability really teaching us?

Moderntechnologies have provoked intense disagreement
between scien7sts who envision a future in which biogene7c
theories will enrich or even replace psychological theories, and
others who consider biogene7c 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 par4ally
heritable and correlated with measurable aspects of brains, but
the very ubiquity of these ndings makes them a poor basis for
reformula7ng scien7sts' concep7ons of human behavior.

Turkheimer Psychol Review 1998

Nuts & Bolts Plan for Today
Nuts & Bolts Plan for Today

Lecture on heritability (Visscher)

Take-home criDcal thinking quesDons
PSYC 210:

The nature & nurture of T&P, Part 1
AJ Shackman
12 March 2015
Conceptual Roadmap for Today

What is heritability?

What is heritability? Students whats your intui4on?

Temperament is oPen conceptualized as biological
and inherited.

e.g., The Malfoys

But just how heritable is T&P? Does it breed true?

Students?

Temperament is oPen conceptualized as biological
and inherited.

e.g., The Malfoys

But just how heritable is T&P? Does it breed true?


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
limitaDons of heritability measures?

What are the prospects for linking heritable traits
(T&P) to discrete systems in the brain?


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 are the limitaDons of heritability
measures?

Four essen4al lessons about

the nature & nurture of T&P
Lesson 1
T&P Reect Both Nature (Genes) and Nurture
(Environment/Experience)
Twin, adopDon and family studies have convincingly shown
that each of the FFM personality dimensions is heritable, with
heritability esDmates 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 variaDon in T&P is NURTURE
Therefore, trait-like individual dierences in T&P are not
biological desDny!
Lesson 1
Gen 2001;

biological desDny!
Lesson 1
Gen 2001;

biological desDny!
Recently, Kandler (2012) provided a more formal synthesis

of previous ndings on age trends in heritability levels of the
two broad trait domains of neuroDcism and extraversion.
Covering studies on age groups from childhood to old age, this
meta-analyDc review revealed decreases in heritability
esDmates of neuroDcism throughout the enDre 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 unDl age 30 years but decreased conDnuously thereafer
(from h2=0.50 to h2 = 0.35 at age 80 years).
Larger Implica4on
Larger Implica4on
Genes (or their absence) do not hard-wire people
for certain behaviors. There is no gene for
understanding calculus [or extraversion or
neuro7cism or self-control]

Specic behaviors are [not biologically] hard-
wired. 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 2010
Larger Implica4on
Genes (or their absence) do not hard-wire people
for certain behaviors. There is no gene for
understanding calculus [or extraversion or
neuro7cism or self-control]

Specic behaviors are [not biologically] hard-
wired. 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 2010
Lesson 2
Genes (nature) can inuence 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

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

(DNA)
Draco Malfoys (ParDally Inherited) Environment
Students What exactly cons4tutes Dracos environment ? Key elements?
Lesson 2
Many measures of the environment are geneDcally
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 inuence on divorce
risk
Lesson 2
Many measures of the environment are geneDcally
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 inuence on divorce risk
Stress of disintegraDng relaDons / 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

-or-

Environment T&P

e.g., chronic stress increases N/NE
Lesson 3

T&P Environment


-or-

Environment T&P

Lesson 3

T&P Environment


-or-

Environment T&P

Lesson 4
Nature is not staDc
Lesson 4
Nature is not staDc
GeneDc inuences (heritability) can change over
development
Individuals gain increased instrumental control over
the environment (e.g., rouDne, occupaDon, spouse)
Over Dme, there is more opportunity for biases and
disposiDons (T&P) to inuence; cumulaDve impact
Lesson 4
Nature is not staDc
GeneDc inuences (heritability) can change over
development
Individuals gain increased instrumental control over
the environment (e.g., rouDne, occupaDon, spouse)
Over Dme, there is more opportunity for biases and
disposiDons (T&P) to inuence; cumulaDve impact
What exactly is heritability?
The [modern] concept of heritabilitywas introducednearly a century ago.

Despite conDnuous misunderstandings and controversiesheritability remains
key to the predicDon of disease risk in medicine
What is heritability (h2)
hops://en.wikipedia.org/wiki/Heritability

A single number indicaDng the % of variaDon
between individuals in a populaDon due to
genotype (pedigree); a raDo of two variances

Total Phenotypic variance (PV) = Genotypic
Variance (GV) + Environmental Variance (EV)
Heritability = GV / PV = fracDon of total variance
in a trait predicted by the pedigree


Total Trait Variance (TTV) = Genotypic Variance
(GV) + Environmental Variance (EV)
Heritability = GV / PV = fracDon of total variance


Total Trait Variance (TTV) = Genotypic Variance
(GV) + Environmental Variance (EV)
Heritability = GV / TTV = fracDon of total variance
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 es4mated??
EsDmaDng heritability (h2)
Family members dier in their degree of geneDc relatedness

You can harness this to esDmate heritability
For example, h2 can be esDmated using the correlaDon
between parent (mean of Mom and Dad) and ospring
phenotypes
Other approaches include the correlaDon between full
siblings or the dierence in the correlaDon of idenDcal (MZ)
and fraternal (DZ) twins

phenotypes

phenotypes

phenotypes

phenotypes
Heritability (h2) esDmates can mislead

If non-trivial, ignoring G*E interacDons deates
h2 (e.g., MDD is not very heritable)

Details are not important

H2 usually ignores G-E correlaDons
the genotype and the phenotype are correlated

e.g., high IQ parents providing enriched environment for ospring;
caole fed in accord with milk producDon
H2 usually ignores G*E interacDons (focusing on addiDve MEs)

the eect of the genotype depends on the environment
e.g., stress x serotonin transporter gene = depression
If non-trivial, ignoring G-E correlaDons inates h2 (e.g., IQ is

really, really heritable)
If non-trivial, ignoring G*E interacDons deates h2 (e.g., MDD is
not very heritable)




the eect of the genotype depends on the environment
e.g., stress x serotonin transporter gene = depression

not very heritable)




the eect of the genotype depends upon the environment
e.g., stress x risky serotonin transporter gene = depression (MDD)

not very heritable)





not very heritable)


H2 usually ignores G-E correlaDons (focusing on addiDve MEs)
caole fed in accord with milk producDon)

Ignoring G-E correlaDons inates h2 (IQ is really, really

heritable)
Ignoring G*E interacDons deates h2 (MDD is not very
heritable)


H2 ignores G-G interacDons
Over-esDmates total heritability
Growing evidence that the impact of parDcular
variants is highly dependent on geneDc context
Eects depend upon what other genes are doing
Huang et al PNAS 2012

variants is highly dependent on geneDc context
Eects depend upon what other genes are doing

These eects bias heritability in dierent
variants is hways
ighly
dependent
on geneDc
context
depending
on how heritability
was
es7mated and the specics of the eect

Eects depend
upon what other genes are doing

HH Goldsmith

Bohom line: Heritability is complex and
e s D m a t e s o P e n e n t a i l s i m p l i f y i n g
assumpDons that may be wrong
Heritability (h2) is not absolute

RaDo (GV/TTV) Made larger by diversifying the geneDc variance &/or

minimizing environmental eects
Sample specic, as with other correlaDons
Social control tends to constrain heritability, whereas heritability is

generally higher under condiDons of low social constraint

e.g., Dierences in disinhibiDon (partying, drinking, and mulDple
sex partners) are not heritable among those raised in a
conservaDve religious environment
No varia4on

e.g., Heritability of smoking in females rose over Dme as it became
more socially acceptable, with no change in men

h2 can dynamically change over lifespan

RaDo (GV/TTV)): Made larger by diversifying the geneDc variance &/or


No TV



RaDo (GV/TTV): Made larger by diversifying the geneDc variance &/or



Increased TV



RaDo (GV/TTV): Made larger by diversifying the phenotypic

variance &/or minimizing environmental eects
Social control reduces heritability; heritability is generally

higher under condiDons of low social constraint

e.g., Dierences in disinhibiDon (partying, drinking, and
mulDple sex partners) are not heritable among those raised
in a conservaDve religious environment

e.g., Heritability of smoking in females rose over Dme as it
became more socially acceptable, with no change in men


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

then smoking
ill not
be a heritable
phenotypic trait
Sample s pecic,
as wwith
other
correlaDons






then smoking
ill not
be a heritable
phenotypic trait
Sample s pecic,
as wwith
other
correlaDons






then smoking
ill not
be a heritable
phenotypic trait
Sample s pecic,
as wwith
other
correlaDons


in a conservaDve religious environment (Amish)



e.g., if EVERYONE smokes or if NO ONE smokes (no variance),

then smoking
ill not
be a heritable
phenotypic trait
Sample s pecic,
as wwith
other
correlaDons


in a conservaDve religious environment (Amish)

became more socially acceptable (no change in men)

4 common misconcepDons
#1
Heritability is the % of a phenotype that is passed
on to the next genera4on. Wrong!

E.g., ~40% of the variaDon in T&P is passed on
no!
Students Why is this wrong?
Genes are passed on, not phenotypes/traits
#1
Heritability is the % of a phenotype that is passed
on to the next genera4on. Wrong!

E.g., ~40% of the variaDon 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 reects the proporDon of variaDon between
individuals (Alex vs. Jee vs. Hannah) in a
Students Why is this wrong?
populaDon that is inuenced by geneDc factors.
h2 describes the populaDon variaDon, not
individuals (Alex) within that populaDon
#2
40% of Alexs T&P is inherited (nature) and 60% is
environmental (nurture). Wrong!

h2 reects the proporDon of variaDon between
individuals (Alex vs. Jee vs. Hannah) in a
populaDon that is inuenced by geneDc factors.
h2 describes the populaDon variaDon, not
individuals (Alex) within that populaDon
#3
High heritability implies gene4c determina4on or des4ny.

Wrong!
High heritability means that most of the variaDon that is
observed is caused by geneDc variaDon
That is, pedigree is a good predictor of a trait in a parDcular pop
Does not mean that the phenotype is xed once we know the
genotype, because the environment can markedly alter the
phenotype
is unavoidable.
It is your ydet
es4ny.
You, like
E.g., 80% of the variaDon in hIt eight
is heritable,
people
your father, are now mine.
around the world have grown
much taller in the face of
improved nutriDon and medical care
#3
High heritability implies gene4c determina4on or des4ny.

Wrong!
High heritability means that most of the variaDon that is
observed is caused by geneDc variaDon
That is, pedigree is a good predictor of a trait in a parDcular pop
Does not mean that the phenotype is xed once we know the
genotype, because the environment can markedly alter the
phenotype
Life Example:
Real
E.g.,
80% of the variaDon in height is heritable, yet people

around the world have grown much taller in the face of
A 70 percent heritability esDmate is prehy wild, said Dr. Krasnegor (NIH).
improved nutriDon and medical care
He said that if it was true, it shouldn't maher too much what you do or
where you go to school. Everything would fall into place.
NY Times, 12 October 1990

#3
High heritability implies gene4c determina4on or des4ny. Wrong!

High heritability means that most of the variaDon that is observed
is caused by geneDc variaDon

Does not mean that the mean phenotype is xed, because the
environment can markedly alter the mean phenotype
E.g., 80+% of the variaDon in height is heritable, yet people
around the world have grown much taller in the past century
because of changes in the environment (improved nutriDon and
medical care)
Heritability describes what is; it does not predict what could be.
Krapohl et al PNAS 2004
#3


medical care)
#3


medical care)
#3

medical care)
#3

medical care)
#3

Furthermore, humans have free will in the face of apparent geneDc

desDny
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 2013b
#3


desDny
But we have the choice to refrain from drinking, to not smoke, and
even to have a prophylaDc mastectomy, even if it runs in our family

X
Xx
x
X
x
#3


desDny
even to have a prophylaDc mastectomy

Xx
x
X
x
#3


desDny
even to have a prophylaDc mastectomy

Like Luke and Angelina,
we can proacDvely
address the problems
that run in our families
X
x
What Does 80% Heritable Even Mean?
High heritability implies gene4c determina4on or
des4ny. Wrong!

80% is misleading:
e.g., for adult human height
h2 = 0.8
Pop SD =~7 cm
the SD of height in adult ospring around the mean value

of their parents is ~5.4 cm
which is only a bit less than the SD in the populaDon
Tall parents on average have tall children, but with

considerable variaDon around the parental mean
High heritability implies gene4c determina4on or
des4ny. Wrong!

80% is misleading:
e.g., for adult human height
h2 = 0.8
Pop SD =~7 cm
the SD of height in adult ospring around the mean value

of their parents is ~5.4 cm
which is only a bit less than the SD in the populaDon
Tall parents on average have tall children, but with

considerable variaDon around the parental mean
Heritability is informa4ve about the nature, origins, or plas4city of mean

dierences across groups or 4me. Wrong!

Heritability is not informaDve about mean changes across groups or Dme
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 reects changes in the environment
Take home: High heritability should not deter the development of intervenDons

#4


Heritability is not informaDve about mean changes across groups or Dme
Height and IQ are highly heritable
Height and IQ have both increased around the world over the past century

2000: US white men were taller than ever before but are now about ~5 cm
This reects changes in the environment
Take home: High heritability should not deter the development of intervenDons

#4


Heritability is not informaDve about mean dierences across groups (e.g.,
races) or Dme (e.g., birth cohorts)
E.g., height and IQ are highly heritable, but they are not xed
Height and IQ have both increased around the world over the past
century

2000: US white men were taller than ever before but are now about ~5 c
This reects changes in the environment (nutriDon, healthcare)
Take home: High heritability should not deter the development of
interven7ons
#4

Example 1: USA vs The Netherlands
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

#4

#4

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 geneDcally similar counterparts in S Korea
#4

about 6 shorter than their geneDcally similar counterparts in S Korea
#4

about 6 shorter than their geneDcally idenDcal relaDves in S Korea
#4

These examples reect dierences in the environment (stress, nutriDon,
healthcare)
Take home: High heritability should not deter the development of
interven7ons and tells us li]le or nothing about the biological origins or
mutability of group (e.g., race) dierences in a phenotype

Family, twin and adopDon studies (FTA)

show that all psychiatric disorders
aggregate in families and are heritable

- Things that relaDves share (genes, diet, peers, SES, toxin exposure)
are important for eDology
- Genes in aggregate have important roles in eDology
- FTA studies are correlaDonal; no insight into underlying molecular
or neural mechanisms
- Kendler notes that because Dx (and T&P traits) are arDcial
categories that do not carve nature at the joints (cf. endo
lecture), showing heritability of The Disorder does not imply a
coherent or unied underlying biological cause


- Things that relaDves share (genes, diet, peers, SES, toxin exposure,
dictators) are important for eDology
lecture), showing heritability of The Disorder or The Trait does not
imply a single coherent or unied underlying biological cause


- Things that relaDves share (genes, diet, peers, SES, toxin exposure,
dictators) are important for eDology
- But FTA studies are correlaDonal; no insight into underlying
molecular or neural mechanisms
- Kendler notes that because diagnoses (like T&P traits) are arDcial
categories that do not carve nature at the joints, simply showing
heritability of The Disorder or The Trait does not imply a single
What are the long-term prospects

for mapping the chain from geneDc
variants to neural intermediates to traits,
such as N/NE, E/PE, or C/SC?

Genome
Intermediate Phenotype
Traits (Evildoing)
To be con4nued next 4me
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 variaDon
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 implicaDons of heritability:

- Highly heritable traits (e.g., height) can be highly amenable to intervenDon. Heritability does
not imply geneDc determinism
- Heritability is probabilisDc: Tall parents, tall kids on average but substanDal spread from kid
to kid
4. Things that relaDves share (genes, diet, peers, SES, toxin exposure) are important for eDology of T&P as
well as Dx
5. Recent GWAS have shown some success, recapitulaDng what we believed based on FTA studies
6. Genes in aggregate have important roles in eDology, but the underlying biological mechanisms remain
unclear (both in terms of specic geneDc polymorphisms and parDcular 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.
8. Switching from heterogeneous, trait-like superfactors and Dxs to simpler endophenotypes may prove
helpful.

1.
2.
3.

to kid
well as Dx
helpful.

1.
2.
3.

to kid
well as Dx
helpful.

1.
2.
3.

to kid
well as Dx
helpful.

1.
2.
3.

to kid
well as Dx
helpful.

1.
2.
3.

to kid
well as Dx
6. Switching from heterogeneous, trait-like superfactors and Dxs to simpler intermediate phenotypes
may prove helpful.
CriDcal Thinking QuesDons

Please select 2 of the op4ons

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 assumpDons 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?(hop://
www.ncbi.nlm.nih.gov/pmc/arDcles/PMC3663891)
2. What are the implicaDons of your newfound understanding of
heritability for intervenDons 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 assumpDons 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?(hop://
www.ncbi.nlm.nih.gov/pmc/arDcles/PMC3663891)
2. What are the implicaDons of your newfound understanding of
heritability for intervenDons 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 geneDcists have convincingly demonstrated

that

Virtually every imaginable kind of behavior is [signicantly]... heritable Once we
accept that basically everythingnot only schizophrenia and intelligence [and T&P],
but also marital status and television watching [and voDng behavior]is heritable, it
becomes clear that specic esDmates of heritability are not very important.

Johnson et al Curr DirecDons Psychol Sci 2010

(see also Turkheimer Psychol Review 1998)

What do you think?

What are the implicaDons of the omnipresence of geneDc eects for your
understanding of the world around you? If everything is somewhat geneDcally
determined (and few things are completely determined), how does it change how
you think about intervenDon or morality (e.g. if BMI/obesity is heritable, should I
diet? If anD-social behavior is heritable, should I press for prisons over rehab
programs?)

1.
2.
X
X

that




What do you think?

understanding of the world around you? If everything is somewhat geneDcally
determined (and few things are completely determined), how does it change how
you think about intervenDon or morality (e.g. if BMI/obesity is heritable, should I
diet? If anD-social behavior is heritable, should I press for prisons over rehab
programs?)

1.
2.
X
X

that




What do you think?

understanding of the world around you? If everything is somewhat biological and
geneDcally determined (and few things are completely determined), how does it
change how you think about intervenDon or morality (e.g. if BMI/obesity is heritable,
should I diet? If anD-social behavior is heritable, should I press for prisons over rehab
programs?)
Time Permiqng

OpDonal Review QuesDons
Kagans model of BI
0%
n
um
be
r o
s a
w
Sh
o
s a
n
um
be
r o
f p
a
f i
m
ra
l
po
...
le
..
0%
Sh
o
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 dierences
from N/NE and Grays BIS,
reinforcing the idea that
childhood temperament
and adult personality are
disDnct kinds
Children with elevated behavioral

inhibiDon (BI)
A.
0%
0%
0%
0%
0%
0%
0%
Ar
e
m
or
Ar
e
e
lik
m
el
or
y
e
Ar
lik to
de
e
el
sh
ve
y

y a
to
l..
d
M
nd
e
ay
ve
sh r et
ice lo..
ow
.
Sh
nt
in
ow ele
va
th
a
te
...
R
d
>
Sh
l
L p
ev
ow
el
at
h
s..
te
ei
.
rn
gh
o
te
f f
ne
..
d
am .
Al
yg
l o
da
f t
..
he
ab
ov
e
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 reDcent in the face of
novelty and potenDal threat (e.g.,
scary robot, human intruder)
D. May show elevated levels of the
stress hormone corDsol
E. Show a R > L paoern of frontal EEG
F. Show heightened amygdala
reacDvity to novel faces in
adulthood
G. All of the above
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B. Micah is an 18 m.o.
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are cute as all get
out
D. All of the above
Anxiety disorders, such as GAD, and

major depression are
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Anxiety disorders, depression, and N/

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amygdala
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Psychological pathogens, such as

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A. The acquisiDon of
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Jerry Kagan argues that the root cause

of childhood behavioral inhibiDon (BI)
is
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(heightened
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sucient to explain the
development of specic
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The RoboGator Experiment: Amygdala

lesions in rodents aoenuate
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tic
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lesioned monkeys and the
human intruder
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hiding in the nest area
(outside the arena
containing the Rgator)
C. All of the above
Amygdala damage
A. Increases raDngs of
trust and
approachability to
faces that are
normally deemed
untrustworthy
B. Has no consequence
of social interacDons
or social cogniDon
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B. A nonspecic risk
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spiders, despite
professing anxiety
B. Shows no fear in the
haunted house
C. Is unable to acquire
new condiDoned
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
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The End
Material to Consider Adding

for Next Semester
This would be awesome to include

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

provide both the genes and the
environment of their children
EvocaDve (ReacDve) - arises
because an individuals social
environment is parDally a funcDon
of how others (not necessarily
family) react to his/her behavior
vs.
AcDve - arises because an individuals

environment is parDally a funcDon of his/her
choices. Is this really a main eect of G?
vs.
Why is G-E CorrelaDon Important?

Familial resemblance in intact nuclear families that is
aoributed to geneDc or environmental factors might
be due to passive G-E correlaDon
Heritable contribuDons on behavioral outcomes
might be due in part to reacDve and acDve G-E
correlaDon eects
G-E correlaDon eects may contribute to the
developmental stability of behavior
G-E correlaDon and its changing nature as children
age is the basis for a theory of development (next
slide)
Goldsmith Slides on Gene4cs,

Eugenics, and Discrimina4on
GeneDc Determinism & GeneDc

DiscriminaDon
The problem may be more
widespread than realized.

Belief in geneDc determinism is a
root cause of geneDc discriminaDon.
Nature of GeneDc Inuence: what

have we learned?
Heritability:
Most human behavioral traits are in part

heritable
Heritability esDmates are
approximaDons
Heritability is not an index of
(non)malleability
Consistent with other topics from the

course
Quote from prominent science

administrator
A 70 percent heritability esDmate is preoy wild,
said Dr. Norman Krasnegor, chief of the Human
Learning and Behavior Branch of the NaDonal
InsDtute of Child Health and Human Development.
He said that if it was true, it shouldn't maher too
much what you do or where you go to school.
Everything would fall into place.''
NY Times, 12 October 1990
A principled criDque of
Behavior GeneDcs
For psychologists, as well as for medical
researchers, the purpose of idenDfying
undesirable predisposiDons of individuals should
be to devise more eecDve health-promoDng
intervenDons, not to discourage such ahempts on
the supposiDon that these predisposiDons are
geneDcally 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
geneDc 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 geneDc
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
hop://www.presidency.ucsb.edu/ws/index.php?pid=52079
Eugenics (Well-Born)
if talented men were mated with talented
women, of the same mental and physical
characters as themselves, generaDon afer
generaDon, 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 ciDzen of the right type is to
leave his or her blood behind him in
the world.
Theodore Roosevelt
Birth control itself, ofen denounced

as a violaDon of natural law, is nothing
more or less than the facilitaDon of
the process of weeding out the unt,
of prevenDng the birth of defecDves or
of those who will become defecDves.
Margaret Sanger
If people are t to live, let them live under

decent human condiDons. If they are not t to
live, kill them in a decent human way.

GBS (1934)
the beher 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
o and sealed up before another year
has passed, W. Churchill (1910)
Demise of the Eugenics Movement

AssociaDon with Nazi movement
Nueld Bioethics Council (2002):
part of the reason for the decline in the support of
eugenic policies in many countries from the 1930s
onward was scienDc research which demonstrated
that the policies of segregaDon and sterilisaDon of
those deemed to be unt 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

In 2000, ~50% of DS cases
were idenDed prenatally
2004 Prenatal Screening
Guidelines
Number of Down Syndrome
Pregnant women oered

risk assessment for DS
> 80% of at-risk had CVS
> 90% of DS cases detected
prenatally
Rate of DS decrease ~50%
Ekelund, C. K., et al. (2008). Impact of a new naDonal screening policy for Down's
syndrome in Denmark: PopulaDon based cohort study. Bri4sh Medical Journal, 337, 7.
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
terminaDons. 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 starDng families at
an older age. Among mothers aged 37 years and older, a
consistent 70% of aected pregnancies were diagnosed
antenatally. In younger mothers, the proporDons of
pregnancies diagnosed antenatally increased from 3% to
43% owing to improvements in the availability and sensiDvity
of screening tests.
What is the most

discriminated against
geneDcally determined
condiDon 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 NeurogeneDc Strategy

Link geneDc variaDon (polymorphisms) to variaDon in brain structure and funcDon (MRI)

Address how genes inuence behavior heritability does not address mechanism!
- by correlaDng geneDc variaDon with intermediate biological phenotypes (e.g., amygdala
acDvaDon), we can discover testable mechanisms for geneDc inuence 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 geneDc polymorphism with a known funcDon (e.g., serotonin transporter SNP)

- and we are willing to make some assumpDons (dierences in the SNP have predictable eects
on gene expression and ulDmately serotonin levels in the amygdala)

- then we can use geneDc variaDon (polymorphisms), which we can noninvasively measure in
humans, as a proxy for individual dierences in neurochemistry (serotonin in the amygdala),

The NeurogeneDc Strategy

Link geneDc variaDon (polymorphisms) to variaDon in brain structure and funcDon (MRI)

Address how genes inuence behavior heritability does not address mechanism!
- by correlaDng geneDc variaDon with intermediate biological phenotypes (e.g., amygdala
acDvaDon), we can discover testable mechanisms for geneDc inuence 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 geneDc polymorphism with a known funcDon (e.g., serotonin transporter)

- and we are willing to make some assumpDons (dierences in the poly. have predictable eects
on gene expression and ulDmately serotonin levels in the amygdala)

- then we can use geneDc variaDon (polymorphisms), which we can noninvasively measure in
humans, as a proxy for individual dierences in neurochemistry (serotonin in the amygdala),

Quick GeneDcs 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 instrucDon
- 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 reacDvity is correlated with variaDon in the
serotonin-transporter linked polymorphic region (5-HTTLPR) on the
SLC6A4 gene
- S allele is bad: Individuals with the less transcripDonally-ecient
short allele (fewer transporter proteins available to clear serotonin
from the synapse) show heightened threat-related amygdala
reacDvity relaDve 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 reacDvity
- Gene Amygdala MDD: Evidence that these geneDcally
conferred dierences in amygdala reacDvity mediate some of the
associaDon between the 5-HTTLPR polymorphism and depression

SLC6A4 gene
reacDvity relaDve 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 reacDvity

SLC6A4 gene
reacDvity relaDve to individuals with the long L allele
- Gene Amygdala: Meta-analyses suggest that 5-HTTLPR accounts
for 2-5% of the variance in amygdala reacDvity

SLC6A4 gene
reacDvity relaDve to individuals with the long L allele
- Gene Amygdala: Meta-analyses suggest that 5-HTTLPR accounts
for 2-5% of the variance in amygdala reacDvity
associaDon between 5-HTTLPR and MDD
The Problem of AssumpDons

These data suggest the following eDologic chain:
[GENETIC OBSERVATION] 5-HTTLPR

[ASSUMPTION] reduced ecacy of 5HTT (protein)

[ASSUMPTION] too much 5HT in amygdala synapses (chemistry)

[NEURAL OBSERVATION] increased amygdala reacDvity to threat

[EPIDEML OBSERVATION] MDD, especially among individuals exposed
to stress
The Problem of AssumpDons

Kalin (UW)

No relaDon between polymorphism and amygdalar 5HTT expression
when you actually go in and measure the transporter using PET

our ndings are in agreement with the majority of human PET
studiesthat suggest there is not adetectable relaDonship 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 quesDon whether this
increased risk is mediated by changes in the expression of the number
of serotonin transporter molecules.
The Problem of Small Eects

- Common polymorphisms have, at most, weak eects on brain
funcDon and behavior (e.g., 2-5%)
- Small eects are hard to detect and likely to result in
nonreplicaDons (false negaDves)
- Prompted the development of large-scale consorDums and data-
sharing networksthousands of subjects across dozens of labs
provides the staDsDcal power needed to reliably detect weak eects
- But this also begs the quesDon of so what why bother if the main
eect of individual geneDc polymorphisms is so small
The G*E Strategy

- Ryan and Ahmad argues that examining G*E interacDons is more
realisDc
- insofar as we believe (e.g., the material covered in prior lectures)
that psychopathology and T&P reect the interacDon of
geneDcally endowed diatheses and negaDve life events (e.g.,
stress, adversity, abuse, loss) and learning
- and not the direct consequence or main eect of either G or E
- Ryan argues that the eects are likely to be bigger as well
The Seminal G*E Example

Gene x Stress: 5-HTTLPR S carriers had a strong and posiDve
relaDonship between life stress and depression, whereas
L carriers did not
Caspi (Duke)
- Proven VERY contenDous (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 interacDon of polymorphisms and life
events on brain structure and funcDon (e.g., 5-HTTLPR x Stress
amygdala MDD)
G*E IllustraDve Examples

Ryan & Ahmad argue that G*E interacDons are likely to play an important role in understanding the inuence of
molecular geneDcs (e.g., 5-HTTLPR) on brain funcDon

But what kinds of eects have the behavioral geneDcists discovered (in aggregate)? What kind of
environmental factors are we likely to be talking about?

- Family Conict Confers Risk: Individuals geneDcally predisposed to low C/SC were even more impulsive in a
conictual family environment;
-
Marriage and Religiosity Confer Resilience: Individuals at geneDc 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: GeneDc risk for developing adolescent
substance use and anDsocial behavior is exaggerated by these environments
Dick summarizes this by noDng that a wide variety of environmental factors can
(a) trigger or
(b) compensate for or regulate the expression of a geneDc predisposiDon

(c) enhance or accentuate a geneDc predisposiDon



- Family Conict Enhances Risk: Individuals geneDcally predisposed to low C/SC were even more impulsive in a
-
Low Parental Monitoring and Substance-Abusing Friends Enhance Risk: GeneDc risk for developing
adolescent substance use and anDsocial behavior is exaggerated by these environments
(a) trigger or
(b) compensate for or regulate the expression of a geneDc predisposiDon

(c) enhance or accentuate a geneDc predisposiDon



- Family Conict Enhances Risk: Individuals geneDcally predisposed to low C/SC were even more impulsive in a
-
Low Parental Monitoring and Substance-Abusing Friends Enhance Risk: GeneDc risk for developing
adolescent substance use and anDsocial behavior is exaggerated by these environments
(a) trigger a geneDc diathesis (e.g., access to substances, life stress, adversity)
(b) compensate for or regulate the expression of a geneDc predisposiDon (e.g., social norms)
(c) enhance or accentuate a geneDc predisposiDon (e.g., delinquent peers)

In principle, you could adopt a similar approach for molecular geneDcs (e.g., 5-HTTLPR)
More SophisDcated Approaches:

Gene*Gene & MulDlocus Proles
The phenotype (T&P/Dx) reects the cumulaDve eect of all the genes; traits
are massively polygenic

In principle, it would be helpful to model gene*gene interacDons or develop
more complex addiDve (many main eects) proles (high on this, medium on
that, low on the other and so on)

In pracDce, this is challenging given the combinatorial complexity

Also, prole scores that combine many genes eliminates the possibility of
tesDng specic mechanisDc hypotheses in animal models, back to black box
of aggregate heritability

There is considerable excitement about the development of more
sophisDcated analyDc tools (e.g., machine learning of phenotypically
interesDng gene proles)

More SophisDcated Approaches:

Gene*Gene & MulDlocus Proles
The phenotype (T&P/Dx) reects the cumulaDve eect of all the genes; traits
are massively polygenic

In principle, it would be helpful to model gene*gene interacDons or develop
more complex addiDve (many main eects) proles (high on this, medium on
that, low on the other and so on)

In pracDce, this is challenging given the combinatorial complexity

Also, prole scores that combine many genes eliminates the possibility of
tesDng specic mechanisDc hypotheses in animal models, back to black box
of aggregate heritability

There is considerable excitement about the development of more
sophisDcated analyDc tools (e.g., machine learning of phenotypically
interesDng gene proles)

NeurogeneDcs Take Homes

1. There is considerable excitement about the neurogeneDcs approach.
2. This reects both clinical interests (Tx) as well as the basic science hope that it can provide clues about the
molecular dierences that inuence the eects seen in fMRI studies (e.g., understand inuence of 5HT
without actually measuring 5HT).
3. But assumpDons may not be warranted; e.g., 5HTTLPR is unrelated to transporter expression in amygdala
4. NeurogeneDcists face all of the problems outlined by Kendler: The Broken Glass, and, The Jet Mechanic. No
guarantee that there are a limited number of funcDonally coherent substrates to be idenDed.
5. The eects of single polymorphisms, such as 5HTTLPR, tend to be weak, necessitaDng large, expensive
samples and begging quesDons about cost/benet.
6. G*E approaches (life stress and 5HTTLPR) have led to much excitement, and may unmask bigger eects and
increased understanding. But at Dmes, it feels like a shing expediDon.
7. Likewise, G*G interacDons (epistasis) and mulDlocus proles that address the aggregate eect of many small-
eect genes may prove helpful, but seem to lead back to the black box of aggregate h2 measures.
8. Combinatorial complexity is daunDng (6M variants!). More sophisDcated modeling and machine learning
approaches will be needed. The primate brain is too stupid to decipher the human brain without help.
9. On the assumpDon that Kendlers Intermediate Scenarios appear most probable, neurogeneDcs appears
useful. Especially when it is integrated with mechanisDc work in nonhuman models (cf. Borsook; Bogdan)
Brief Aside on How the Environment

Gets Under the Skin

Students:
whats a plausible mechanism?

How might paren4ng or exposure to
other risks inuence behavior
(phenotype)?
How Does E Get Under the Skin?

EpigeneDcs provides a biological explanaDon for how E (parenDng, 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 inuenced by transcripDon factors, which bind to sequences of DNA
Binding of transcripDon factors turns genes on or o
EpigeneDc mechanisms involve changes to how readily transcripDon factor can access the DNA
- E.g., methylaDon: addiDon of a methyl group onto a cytosine (1 of the 4 base

pairs that make up DNA) silences the gene because methyl hinders the transcripDon factors

EpigeneDc modicaDons 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 dierent genes are acDve in liver cells vs.
neurons
Work in rodents by Michael Meaneys group demonstrates that maternal behavior can inuence the adult T&P
of ospring and that this is epigeneDc dependent


-


neurons
Work in rodents by Michael Meaneys group demonstrates that maternal behavior (x-fostered) can inuence
the adult T&P of ospring and that this is epigeneDc dependent


-


neurons
Elegant mechanisDc work in rodents by Michael Meaneys group demonstrates that one aspect of the early
environment , maternal behavior (x-fostered), can inuence the T&P of ospring and that this is epigeneDc
dependent
This is exceedingly hard to study in humans because epigeneDc mechanisms vary across the brain and body, so
measuring epigeneDc eects in blood or saliva may not tell you very much about the amygdala
PSYC 612 R08B:

G-E Correla4ons:
How Genes Get Outside the Skin

AJ Shackman
9 December 2013
PSYC 612 R08B:

G-E Correla4ons:
How Genes Get Outside the Skin

Students?
Lemery (ASU)
Jaee (Penn)
G-E CorrelaDons Dened (Plomin 77)

Many sources of inuence that we might consider environmental are actually non-random and geneDc

1. Passive G-E correlaDon (nature and nurture are confounded)
- among biologically related parents and ospring, the parents provide genotypes AND rearing
environment; thus many parent-child outcome correlaDons may actually reect passive G-E eects
-
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 geneDc risk for aggressive behavior (common cause)

2. EvocaDve G-E correlaDon
- e.g., a child who is predisposed to having an outgoing, cheerful T&P is more likely to evoke posiDve
aoenDon 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. AcDve G-E correlaDon
- Individuals acDvely select environments
- E.g., individuals predisposed to high E/PE seeking may be more prone to aoend parDes, go to bars, meet
new people, be exposed to or to try substances of abuse


environment; thus many parent-child outcome correlaDons reect passive G-E eects
-

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



-

-
E.g., Infant behavioral inhibiDon evokes parental insensiDvity, which then potenDates
maladapDve parentchild interacDons over Dme, exacerbaDng fear of novelty



-

-
E.g., Infant behavioral inhibiDon evokes parental insensiDvity, which then potenDates
maladapDve parentchild interacDons over Dme, exacerbaDng fear of novelty

3. AcDve G-E correlaDon (Niche Building)
-
E.g., individuals predisposed to high E/PE seeking may be more prone to aoend parDes, go to bars, meet
new people, be exposed to delinquent peers, and try substances of abuse
Evidence for G-E CorrelaDons

Mostly from FTA studies demonstraDng that environmental measures are heritable, including many linked to
psychopathology

e.g., marital quality, social support, parental discipline/warmth, family environment, peer relaDonships,
negaDve life events such as divorce and exposure to trauma

Environments are heritable because genotype inuences behaviors that evoke, select, and modify features of
the environment

- Environments less amenable to behavioral modicaDon 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, geng red

Take home: GeneDc risk factors do not necessarily have direct eects on phenotypes (T&P, Dx), but can work
indirectly by modifying sensiDvity to environmental risk factors (acDve G-E) or by inuencing exposure
to risk (passive, evocaDve G-E)


Mostly from FTA studies demonstraDng that environmental measures are heritable, including many linked to
psychopathology

e.g., marital quality, social support, parental discipline/warmth, family environment, peer relaDonships,
negaDve life events such as divorce and exposure to trauma

Environments are heritable because genotype inuences behaviors that evoke, select, and modify features of
the environment

- Environments less amenable to behavioral modicaDon 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, geng red

Take home: GeneDc risk factors do not necessarily have direct eects on phenotypes (T&P, Dx), but can work
indirectly by modifying sensiDvity to environmental risk factors (acDve G-E) or by inuencing exposure
to risk (passive, evocaDve G-E)

G-E CorrelaDon Take Homes

3 Kinds of G-E CorrelaDons: Passive, EvocaDve, and AcDve

Take home: GeneDc risk factors do not necessarily have direct eects
on phenotypes (T&P, Dx), but can work indirectly by modifying
exposure to environmental risks (e.g., stress, substances, delinquent
peers) that reinforce parDcular personality traits or precipitate frank
psychopathology

More fundamentally, these data emphasize that Nature/Genotype and
Nurture/Environment are not mutually exclusive forces, but ofen 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 hypofuncDon (shrunken
dendrites, too few or dysfuncDonal receptors, downregulated 2nd
messenger systems, or decient transport mechanisms.

There are even more pathways to make a complex
circuit dysfuncDon

This scenario is likely if there are hundreds of disDnct biochemical
changes that individually contribute to Dx (neither necessary nor
sucient) 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 hallucinaDons, grandiosity) for a limited
number of biologically coherent pathways to emerge from the 100s or 1000s of genes that
make small contribuDons 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 ndings.

If so, then a geneDc 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 J

In the most opDmisDc scenario, nearly all of the veried risk genes idenDed through GWAS or
sequencing will map to a single coherent inter-connected biological pathway.

This will occur only if the geneDc underpinnings of the disorder reect a high degree of
eDological homogeneity. i.e. a single disease process (equinality)

Intermediate scenarios (neither Ugly nor Good) are possible

Strategy for Linking FTA to Molecules

Dick notes that it is useful to rst search for G*E interacDons in FTA studies

There are a huge number of environmental factors that could potenDally be assessed

Useful to build o the already well-developed developmental literature

In cases where there is an interacDon 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 specic genes, either candidate variants or GWAS
The Broad Goal

Kendler underscored our ignorance about the biology linking genotypes to phenotypes.

Developing a mechanisDc understanding of the neurobiology of T&P and their associated psychiatric
disorders would allow us to:

- Redene diagnosDc categories and T&P traits in terms of quanDable eDology (root causes)
- Develop novel treatments or prevenDon eorts targeDng links in the eDological chain
- IdenDfy at-risk individuals early (e.g., carriers of a parDcular polymorphism)
- Predict treatment response (e.g., carriers of a parDcular polymorphism)
- Monitor treatment in terms of changes in the underlying neural systems
TranslaDonal Promise

Sara argues that, in principle, if one could idenDfy with high sensiDvity and specicity at-risk G-E pairs

- At-risk kids paired with risky environments (parental style, peers, adversity, abuse, etc.)

You could target them for precision intervenDons BEFORE the onset of cumulaDve damage

- in eect, she argues for a more nuanced extension of the Moo PNAS strategy

- instead of idenDfying kids with low C/SC

- idenDfy 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-opDmal skill)

- potenDally, one could use biomarkers (gene screens) to idenDfy high-risk parent-kid dyads

Some Success with GWAS

- GWAS: Genome wide associaDon study
- brute force approachtesDng one-by one the correlaDon between
traits and hundreds of thousands of common geneDc variants
- the opposite of candidate gene studies that uDlize theories to test
a small number of geneDc variants
- GWAS treats every common genomic variant the same, allowing
detecDon of pathogenic variants never previously conceived of

- Penalty is low power, due to correcDon for mulDple comparisons
- Trade o is beginning to pay o.
Some Success with GWAS

Very recent GWASs have idenDed sets of polymorphisms that
collecDvely account for much of the heritability of major psychiatric
disorders

e.g., 32% variaDon in MDD (phenotype) can be explained by
individual polymorphisms (genes)
- Suggests that a substanDal proporDon of geneDc variaDon results
from very large numbers of small eect 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 ObjecDves

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 limitaDon of this parameter? What are common
misconcepDons about h2?
3. What has psychiatric geneDcs taught us?
4. What are the long-term prospects for linking heritable traits (e.g., T&P) to disDnct
neurobiological systems?
5. There is a considerable excitement about so-called neurogeneDc approaches that
combine measures of molecular geneDc variaDon (SNPs) with measures of brain funcDon
(fMRI). What are the seminal observaDons? What are some of the key challenges facing
the nascent eld of neurogeneDcs?
6. What are G*E interacDons? How does geneDc inuence depends on the environment?
7. How does the environment get under the skin?
8. What are the 3 kinds of G-E correlaDons? What is the fundamental implicaDon of G*E
interacDon and G-E correlaDons for the Nature vs. Nurture dichotomy
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 hallucinaDons) for a limited number of
biologically coherent pathways to emerge from the 1000s of genes that make small
contribuDons to risk.

If so, then a geneDc 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)



lecture), showing heritability of The Disorder does not imply a


lecture), showing heritability of The Disorder or The Trait does not
imply a single coherent or unied underlying biological cause


- Kendler notes that because diagnoses (like T&P traits) are arDcial
categories that do not carve nature at the joints
- Showing heritability of The Disorder or The Trait does not imply a
single coherent or unied underlying biological cause
What are the long-term prospects

for mapping the chain from geneDc
variants to neural intermediates to traits,
such as N/NE, E/PE, or C/SC?

Genome
Intermediate Phenotype
Traits (Evildoing)
Kendler oers 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 systemreects an emergent property of
many, many genes acDng together that constructs a glass that is either stress sensiDve or
resistant.

Now imagine that we have a machine deliver a hammer-blow (aka a criDcal 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 systemreects an emergent property of
many, many genes acDng together that constructs a glass that is either stress sensiDve or
resistant.

Now imagine that we have a machine deliver a hammer-blow (aka a criDcal life stressor) such
that a set percentage of the glasses break (aka develop illness).

Ugly Scenario

Each glass that breaks shaoers in its own unique way.

If this is true, we shall have a very hard Dme geng a single reliable set of genes, there are too
many dierent 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 Dme 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 knioed 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 shaoer 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 sucient 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 ying well.

A 747 has six million parts, about the number of common variants in the human genome.

You carefully screen all 6M parts and idenDfy 50 broken ones


was not ying well.



Ugly Scenario: The 50 parts come from enDrely dierent systems of the aircraf. You cannot
see any paoern. 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.

was not ying well.




Good Scenario: You realize that although spread out over several areas of the plane and
reecDng dierent subsystems, all 50 broken parts play an important role in one func7onal
system in the airplanethe funcDoning of the wing aps. The ap xers (Big Pharma) are
ecstaDc.

was not ying well.




Good Scenario: You realize that although spread out over several areas of the plane and
reecDng dierent subsystems, all 50 broken parts play an important role in one func7onal
system in the airplanethe funcDoning of the wing aps. The ap xers (Big Pharma) are
ecstaDc.

Intermediates: 40 of the 50 broken parts come from 3 unrelated systems
Or
You discover 4 sets of broken parts3 to 5 parts eachthat reect individual sub-systems. But
most of the parts seem random and cannot be meaningfully linked together in any useful way.

These laoer 2 scenarios are more likely than The Good or The Ugly ones.

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If

everything is heritable, what is heritability really teaching us?

Nuts & Bolts Plan for Today

Nuts & Bolts Plan for Today

Take-home criDcal thinking quesDons

Conceptual Roadmap for Today

Conceptual Roadmap for Today

Conceptual Roadmap for Today

Conceptual Roadmap for Today

But just how heritable is T&P? Does it breed true?

Conceptual Roadmap for Today

But just how heritable is T&P? Does it breed true?

Conceptual Roadmap for Today

Conceptual Roadmap for Today

Four essen4al lessons about

Recently, Kandler (2012) provided a more formal synthesis

Draco Malfoys Genes

Draco Malfoy, Across Early Development

Draco Malfoys Genes

Draco Malfoys Genes

Draco Malfoys (ParDally Inherited) Environment

Draco Malfoys Genes

Draco Malfoys (ParDally Inherited) Environment

Students What exactly cons4tutes Dracos environment ? Key elements?

e.g., Genes for NE/N life-events, such as divorce

What exactly is heritability?

The [modern] concept of heritabilitywas introducednearly a century ago.

What is heritability (h2)

What is heritability (h2)

What is heritability (h2)

What is heritability (h2)

How well can you predict Ginnys hair

Whadya mean the % of variance in the

EsDmaDng heritability (h2)

Family members dier in their degree of geneDc relatedness

EsDmaDng heritability (h2)

Family members dier in their degree of geneDc relatedness

EsDmaDng heritability (h2)

Family members dier in their degree of geneDc relatedness

EsDmaDng heritability (h2)

Family members dier in their degree of geneDc relatedness

EsDmaDng heritability (h2)

Family members dier in their degree of geneDc relatedness

Heritability (h2) esDmates can mislead

Heritability (h2) esDmates can mislead

the genotype and the phenotype are correlated

H2 usually ignores G*E interacDons (focusing on addiDve MEs)

If non-trivial, ignoring G-E correlaDons inates h2 (e.g., IQ is

Heritability (h2) esDmates can mislead

the genotype and the phenotype are correlated

H2 usually ignores G*E interacDons (focusing on addiDve MEs)

If non-trivial, ignoring G-E correlaDons inates h2 (e.g., IQ is

Heritability (h2) esDmates can mislead

the genotype and the phenotype are correlated

H2 usually ignores G*E interacDons (focusing on addiDve MEs)

If non-trivial, ignoring G-E correlaDons inates h2 (e.g., IQ is

Heritability (h2) esDmates can mislead

the genotype and the phenotype are correlated

H2 usually ignores G*E interacDons (focusing on addiDve MEs)

If non-trivial, ignoring G-E correlaDons inates h2 (e.g., IQ is

Heritability (h2) esDmates can mislead

H2 usually ignores G*E interacDons (focusing on addiDve MEs)

Ignoring G-E correlaDons inates h2 (IQ is really, really

Heritability (h2) esDmates can mislead