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

Conceptual Roadmap for Today What is heritability?

Conceptual Roadmap for Today What is heritability? Students whats your intui4on?

Conceptual Roadmap for Today Temperament is oPen conceptualized as biological and inherited. e.g., The Malfoys

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

Students?

Conceptual Roadmap for Today Temperament is oPen conceptualized as biological and inherited. e.g., The Malfoys

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

Conceptual Roadmap for 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 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?

Conceptual Roadmap for Today

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!

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?



Draco Malfoys (ParDally Inherited) Environment



Draco Malfoys (ParDally Inherited) Environment

Students What exactly cons4tutes Dracos environment ? Key elements?

Lesson 2 Genes (nature) can inuence environments (nurture) 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 Genes (nature) can inuence environments (nurture) 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 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

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 in a trait predicted by the pedigree




Total Trait Variance (TTV) = Genotypic Variance (GV) + Environmental Variance (EV)

Heritability = GV / TTV = fracDon of total variance in a trait predicted by the pedigree



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??

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

EsDmaDng heritability (h2)

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

Heritability (h2) esDmates can mislead

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)



H2 usually ignores G-E correlaDons


caole fed in accord with milk producDon

H2 usually ignores G*E interacDons (focusing on addiDve MEs) the eect of the genotype depends upon the environment e.g., stress x risky serotonin transporter gene = depression (MDD)

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



H2 usually ignores G-E correlaDons (focusing on addiDve MEs)


caole fed in accord with milk producDon)

H2 usually ignores G*E interacDons (focusing on addiDve MEs) the eect of the genotype depends upon the environment e.g., stress x risky serotonin transporter gene = depression (MDD)

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

X


Huang et al PNAS 2012

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

X


Huang et al PNAS 2012

These eects bias heritability in dierent ways depending on how heritability was es7mated and the specics of the eect

HH Goldsmith Bohom line: Heritability is complex and e sDmates oPen en ta i l s imp l i f y ing 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

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


No varia4on

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







No TV

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







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., if EVERYONE smokes or if NO ONE smokes, then smoking will not be a heritable phenotypic trait




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




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




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

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



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

4 common misconcepDons

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

#1

Students Why is this wrong?

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

#1

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

#2

Students Why is this wrong?

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

#2

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

E.g., 80% of the variaDon in height is heritable, yet people around the world have grown much taller in the face of improved nutriDon and medical care

#3

It is unavoidable. It is your des4ny. You, like your father, are now mine.



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

E.g., 80% of the variaDon in height is heritable, yet people around the world have grown much taller in the face of improved nutriDon and medical care

#3

Real Life Example: A 70 percent heritability esDmate is prehy wild, said Dr. Krasnegor (NIH). 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



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



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

#3

Kendler Mol Psych 2013b

High heritability implies gene4c determina4on or des4ny. Wrong! 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

#3




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




But we have the choice to refrain from drinking, to not smoke, and even to have a prophylaDc mastectomy Xx x

X x

#3




But we have the choice to refrain from drinking, to not smoke, and 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


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


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 informa4ve about the nature, origins, or plas4city of mean dierences across groups or 4me. Wrong! 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 shorter than Dutch men. Go Orange!

This reects changes in the environment (nutriDon, healthcare)

Take home: High heritability should not deter the development of interven7ons

#4

Heritability is informa4ve about the nature, origins, or plas4city of mean dierences across groups or 4me. 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


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


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 idenDcal relaDves in S Korea

#4

Heritability is informa4ve about the nature, origins, or plas4city of mean dierences across groups or 4me. Wrong! 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

#4

- 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

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,

dictators) are important for 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 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 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 Traits (Evildoing) Intermediate Phenotype

To be con4nued next 4me

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.

Some Take Homes on Nature/Nurture





to kid



6. 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.

7. Switching from heterogeneous, trait-like superfactors and Dxs to simpler endophenotypes may prove helpful.






to kid



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. X 2. 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. X 2. 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 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 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

Shows a number of paralle..

Shows a number of impo...

0%0%

Children with elevated behavioral inhibiDon (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 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 Are m

ore likely to devel..

Are m

ore likely to develo...

Are shy and reticen

t in th...

May show elevated levels...

Show a R > L p

attern

of f...

Show heighten

ed am

ygda..

All of the above

0% 0% 0% 0%0%0%0%

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 Hannah is a 6 y.o. boy

Micah is an 18 m

.o. girl

Both of Dr. Ss kids are cu..

All of the above

0% 0%0%0%

Anxiety disorders, such as GAD, and major depression are

A. Categorically dierent

B. Ofen co-morbid and show a number of other similariDes, in terms of therapeuDc response, heritability, and do on, suggesDng that they are closely related to one another and form a spectrum Categ

orically different

Often

co-morb

id and sho...

0%0%

Treatments targeDng anxiety disorders

A. Tend to inuence N/NE as well as depression

B. SelecDvely inuence the targeted disorder

C. Only help some paDents

D. A and C E. B and C

Tend to influence N/NE a...

Selectively influence the ...

Only help some patients

A and C

B and C

0% 0% 0%0%0%

Anxiety disorders, depression, and N/NE appear to share

A. Genes B. Neural substrates

(e.g., amygdala hyper-reacDvity)

C. Both

Genes

Neura

l substrates (e.g.,... Bo

th

0% 0%0%

Lesion studies in rodents, monkeys, and humans demonstrate that the

amygdala A. Is required for the

normal acquisiDon of new fear learning (condiDoned emoDonal response)

B. Not required C. Is required for the

retenDon of already learned fears

Is required for the norma...

Not required

Is required for the reten

t...

0% 0%0%

Elevated N/NE

A. Is common among anxiety paDents

B. Is common among depression paDents

C. Both

Is com

mon amo

ng anxiet...

Is com

mon amo

ng depre

... Both

0% 0%0%

Psychological pathogens, such as stress and family conict

A. Exert similar eects on depression, anxiety disorders, and N/NE, suggesDng a common substrate

B. Have disDnct eects on T&P vs. depression vs. anxiety disorders

Exert sim

ilar effects on

...

Have distinct effects on

...

0%0%

Amygdala lesions in monkeys block

A. The acquisiDon of new condiDoned fears

B. Innate anxiety about snakes

C. Both

Jerry Kagan argues that the root cause of childhood behavioral inhibiDon (BI)

is A. An over-reacDve

amygdala B. MaladapDve

cogniDve coping mechanisms

C. Worry D. Disress E. Social reDcence F. Shyness

An over-reactive am

ygdala

Maladaptive cognitive co...

Worry

Disress

Social reticence

Shyness

0% 0% 0%0%0%0%

The administraDon of a benzodiazepine (anD-anxiety

medicaDon) A. Causes a dose-

dependent reducDon in amygdala acDvaDon

B. Causes a dose-dependent increase in amygdala acDvaDon

Causes a dose-d

ependent...

Causes a dose-d

ependent...

0%0%

Why do some individuals develop parDcular disorders, such as specic phobia of dogs? A. Learning and experience B. Core vulnerability

(heightened neuroDcism, hyper-reacDve amygdala, inadequate regulaDon of the amygdala)

C. Both, neither is sucient to explain the development of specic emoDonal disorders Learn

ing an

d experience

Core vulne

rability (heigh...

Both, ne

ither is s

ufficient...

0% 0%0%

The RoboGator Experiment: Amygdala lesions in rodents aoenuate

A. ReDcence to get the food pellet in the presence of the remote-control robogator, suggesDng a substrate for the reDcence demonstrated by BI kids, consistent with lesioned monkeys and the human intruder

B. The amount of Dme hiding in the nest area (outside the arena containing the Rgator)

C. All of the above Reticence to get th

e food...

The amo

unt of time

hidin...

All of the above

0% 0%0%

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

Increa

ses ratings of tru

st...

Has no conseq

uence o

f so...

0%0%

N/NE is

A. A specic risk factor for anxiety disorders

B. A nonspecic risk factor for a broad range of psychiatric disease

A specific risk facto

r for a...

A nonspecific risk factor f..

0%0%

PaDent SM has circumscribed bilateral destrucDon 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 condiDoned fears in the lab

D. Quickly returned to the park where she was assaulted

Picks up snakes and spide...

Shows no fear in

the hau...

Is unable to acquire new...

Quickly return

ed to the ...

0% 0%0%0%

Is BI a viable intermediate phenotype for social anxiety disorder

A. Yes B. No

Yes No

0%0%

EmoDonal disorders and N/NE

A. Are fundamentally dierent

B. Reect a common cause

C. Are categorically disDnct

Are fundame

ntally differen

t

Reflect a com

mon cause

Are cate

gorically distinct

0% 0%0%

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

Genotype-Environment CorrelaDon EvocaDve (ReacDve) - arises because an individuals social environment is parDally a funcDon of how others (not necessarily family) react to his/her behavior

Genotype-Environment CorrelaDon

AcDve - arises because an individuals environment is parDally a funcDon of his/her choices. Is this really a main eect of G?

vs.

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

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)

Eugenics (Well-Born)

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 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.

Number of Down Syndrome

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

outlawed in 1994

NEW YORK, SUNDAY, APRIL 22, 2001

most common among educated women

Extra Slides

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),

The NeurogeneDc Strategy

- 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.

Quick GeneDcs Tutorial

- 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

Seminal Example: Amygdala & 5-HTTLPR


- 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 L allele

- Gene Amygdala: Meta-analyses suggest that 5-HTTLPR 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



- 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 L allele

- Gene Amygdala: Meta-analyses suggest that 5-HTTLPR 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 5-HTTLPR and MDD


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

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 AssumpDons

Kalin (UW)

- 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 Problem of Small Eects

- 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 G*E Strategy

Gene x Stress: 5-HTTLPR S carriers had a strong and posiDve relaDonship between life stress and depression, whereas L carriers did not

- 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)

The Seminal G*E Example

Caspi (Duke)

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

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 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

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


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 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

Dick summarizes this by noDng that a wide variety of environmental factors can (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)


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

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)

NeurogeneDcs Take Homes

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)?

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

How Does E Get Under the Skin?








- 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









- 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)

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

G-E CorrelaDons Dened (Plomin 77)


- among biologically related parents and ospring, the parents provide genotypes AND rearing 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., a child who is predisposed to having an outgoing, cheerful

shackman psyc210 module10 naturenurture part1 031215

Documents

heritable traits tp

conceptual roadmap

tp reect

heritability esdmates

terms of heritability

nature nurture of tp

heritable vinkhuyzen

turkheimer et