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PSYC 210:
The nature & nurture of T&P, Part 2
Molecular substrates of trait-like differences with a focus on
Gene-Environment Interactions
AJ Shackman
March 2015
Conceptual Roadmap
T&P are somewhat heritable
What molecular mechanisms account for
that heritability?
T&P reflects the influence of both genetic
inheritance (nature) and the
environment/experience (nurture)
Are these separate effects (G and E) or an
interaction (G x E)?
e.g., Exposure to stress and risky genes
Conceptual Roadmap
T&P are somewhat heritable
What molecular mechanisms account for
that heritability?
T&P reflects the influence of both genetic
inheritance (nature) and the
environment/experience (nurture)
Are these separate effects (G and E) or an
interaction (G x E)?
e.g., Exposure to stress and risky genes
Conceptual Roadmap
T&P are somewhat heritable
What molecular mechanisms account for
that heritability?
T&P reflects the influence of both genetic
inheritance (nature) and the
environment/experience (nurture)
Are these separate and independent effects
(G and E) or an interaction (G x E)?
e.g., Risky genes AND stress exposure
DNA
Genes
DNA Chromosomes
- 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
DNA Chromosomes
- 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
https://en.wikipedia.org/wiki/Human_genom
Genes
https://en.wikipedia.org/wiki/Human_genom
Genes
https://en.wikipedia.org/wiki/Human_genom
Genes
https://en.wikipedia.org/wiki/Human_genom
Genes
https://en.wikipedia.org/wiki/Human_genom
What makes us
different?
Patients (Cases)
Allele #1
Allele #2
% Allele #1
90%
tp://vassarstats.net/odds2x2.html
Patients (Cases)
Controls
Allele #1
Allele #2
% Allele #1
90%
10%
tp://vassarstats.net/odds2x2.html
Patients (Cases)
Controls
Allele #1
Allele #2
% Allele #1
90%
10%
Allele #1 is associated
with a 9x increased risk
of disease!
(risk ratio)
GWAS
- GWAS: genome-wide association study (repeat for
>1M common SNPs)
- Example: Individuals with the G-allele of SNP1
(rs1333049) were overrepresented amongst patients
(upper row) vs. controls
GWAS
- GWAS: genome-wide association study (repeat for
>1M common SNPs)
SNP1
Patients
Controls
SNP2
Etc.
SNP Chip
SNP Chip
SNP Chip
SNP Chip
SNP Chip
SNP Chip
Measure binding
Array of probes for
different gene variants
SNP Chip
Measure binding
Array of probes for
different gene variants
GWAS
- Brute force approachtesting one-by one the
correlation between traits and hundreds of thousands
of common genetic variants
- GWAS treats every common genomic variant the same,
allowing the discovery of novel trait- or disease
relevant genetic variants in the absence a priori
hypotheses
- The opposite of candidate gene studies that utilize
theories to test a small number of genetic variants
- Penalty is low statistical power and sensitivity, due to
correction for millions of tests across the genome
- Furthermore, GWAS will miss rare genetic variants
because they are not included on the SNP chip arrays
GWAS
- Brute force approachtesting one-by one the
correlation between traits and hundreds of thousands
of common genetic variants
- GWAS treats every common genomic variant the same,
allowing the discovery of novel trait- or disease
relevant genetic variants in the absence a priori
hypotheses
- The opposite of candidate gene studies that utilize
theories to test a small number of genetic variants
- Penalty is low statistical power and sensitivity, due to
correction for millions of tests across the genome
- Furthermore, GWAS will miss rare genetic variants
because they are not included on the SNP chip arrays
GWAS
- Brute force approachtesting one-by one the
correlation between traits and hundreds of thousands
of common genetic variants
- GWAS treats every common genomic variant the same,
allowing the discovery of novel trait- or disease
relevant genetic variants in the absence a priori
hypotheses
- The opposite of candidate gene studies that utilize
theories to test a small number of genetic variants
- Penalty is low statistical power and sensitivity, due to
correction for millions of tests across the genome
- Furthermore, GWAS will miss rare genetic variants
because they are not included on the SNP chip arrays
GWAS
- Brute force approachtesting one-by one the
correlation between traits and hundreds of thousands
of common genetic variants
- GWAS treats every common genomic variant the same,
allowing the discovery of novel trait- or disease
relevant genetic variants in the absence a priori
hypotheses
- The opposite of candidate gene studies that utilize
theories to test a small number of genetic variants
- Penalty is low statistical power and sensitivity, due to
correction for millions of tests across the genome
(p<.05 p<.05/1,000,000)
- Furthermore, GWAS will miss rare genetic variants
GWAS
- Brute force approachtesting one-by one the
correlation between traits and hundreds of thousands
of common genetic variants
- GWAS treats every common genomic variant the same,
allowing the discovery of novel trait- or disease
relevant genetic variants in the absence a priori
hypotheses
- The opposite of candidate gene studies that utilize
theories to test a small number of genetic variants
- Penalty is low statistical power and sensitivity, due to
correction for millions of tests across the genome
(p<.05 p<.05/1,000,000)
- Furthermore, GWAS will miss rare genetic variants
Why bother?
The Premise
We are pretty ignorant about the biology linking genotypes to phenotypes
(e.g., N, E, and SC). So its difficult to generate good hypotheses (candidate
genes to examine).
If we could somehow harness genetics to understand the molecular
neurobiology of T&P and associated psychiatric disorders, it would enable us
to:
-
Redefine diagnostic categories and T&P traits in terms of quantifiable etiology (root
causes)
Develop novel treatments or prevention efforts targeting links in the etiological chain
Precision medicine: Predict treatment response or more quickly pick the best treatment
(e.g., carriers of a particular polymorphism)
Provide a novel discovery tool for addressing some of the most fundamental question
about the nature of T&P
- Where does extraversion come from?
The Premise
We are pretty ignorant about the biology linking genotypes to phenotypes
(e.g., N, E, and SC). So its difficult to generate good hypotheses (candidate
genes to examine).
If we could somehow harness genetics to understand the molecular
neurobiology of T&P and associated psychiatric disorders, it would enable us
to:
-
Redefine diagnostic categories and T&P traits in terms of quantifiable etiology (root
causes)
Develop novel treatments or prevention efforts targeting links in the etiological chain
Precision medicine: Predict treatment response or more quickly pick the best treatment
(e.g., carriers of a particular polymorphism)
Provide a novel discovery tool for addressing some of the most fundamental question
about the nature of T&P
- Where does extraversion come from?
The Premise
We are pretty ignorant about the biology linking genotypes to phenotypes
(e.g., N, E, and SC). So its difficult to generate good hypotheses (candidate
genes to examine).
If we could somehow harness genetics to understand the molecular
neurobiology of T&P and associated psychiatric disorders, it would enable us
to:
-
Redefine diagnostic categories and T&P traits in terms of quantifiable etiology (root
causes)
Develop novel treatments or prevention efforts targeting links in the etiological chain
Predict treatment response or more quickly pick the best treatment (e.g., carriers of a
particular polymorphism).personalized or precision medicine
Enhance prognosis: You (and other carriers of SNP X) have 3 months to live
Provide a novel discovery tool for addressing some of the most fundamental question
about the nature of T&P
- Where does extraversion come from?
-
The Premise
We are pretty ignorant about the biology linking genotypes to phenotypes
(e.g., N, E, and SC). So its difficult to generate good hypotheses (candidate
genes to examine).
If we could somehow harness genetics to understand the molecular
neurobiology of T&P and associated psychiatric disorders, it would enable us
to:
-
Redefine diagnostic categories and T&P traits in terms of quantifiable etiology (root
causes)
Develop novel treatments or prevention efforts targeting links in the etiological chain
Predict treatment response or more quickly pick the best treatment (e.g., carriers of a
particular polymorphism).personalized or precision medicine
Enhance prognosis: You (and other carriers of SNP X) have 3 months to live
Provide a novel discovery tool for addressing some of the most fundamental question
about the nature of T&P
- Where does extraversion come from?
-
The Premise
We are pretty ignorant about the biology linking genotypes to phenotypes
(e.g., N, E, and SC). So its difficult to generate good hypotheses (candidate
genes to examine).
If we could somehow harness genetics to understand the molecular
neurobiology of T&P and associated psychiatric disorders, it would enable us
to:
-
Redefine diagnostic categories and T&P traits in terms of quantifiable etiology (root
causes)
Develop novel treatments or prevention efforts targeting links in the etiological chain
Predict treatment response or more quickly pick the best treatment (e.g., carriers of a
particular polymorphism).personalized or precision medicine
Enhance prognosis: You (and other carriers of SNP X) have 3 months to live
Provide a novel discovery tool for addressing some of the most fundamental question
about the nature of T&P
- Where does extraversion come from?
-
The Premise
We are pretty ignorant about the biology linking genotypes to phenotypes
(e.g., N, E, and SC). So its difficult to generate good hypotheses (candidate
genes to examine).
If we could somehow harness genetics to understand the molecular
neurobiology of T&P and associated psychiatric disorders, it would enable us
to:
-
Redefine diagnostic categories and T&P traits in terms of quantifiable etiology (root
causes)
Develop novel treatments or prevention efforts targeting links in the etiological chain
Predict treatment response or more quickly pick the best treatment (e.g., carriers of a
particular polymorphism).personalized or precision medicine
Enhance prognosis: You (and other carriers of SNP X) have 3 months to live
Provide a novel discovery tool for addressing some of the most fundamental question
about the nature of T&P
- Where does extraversion come from?
-
The Premise
We are pretty ignorant about the biology linking genotypes to phenotypes
(e.g., N, E, and SC). So its difficult to generate good hypotheses (candidate
genes to examine).
If we could somehow harness genetics to understand the molecular
neurobiology of T&P and associated psychiatric disorders, it would enable us
to:
-
Redefine diagnostic categories and T&P traits in terms of quantifiable etiology (root
causes)
Develop novel treatments or prevention efforts targeting links in the etiological chain
Predict treatment response or more quickly pick the best treatment (e.g., carriers of a
particular polymorphism).personalized or precision medicine
Enhance prognosis: You (and other carriers of SNP X) have 3 months to live
Provide a novel discovery tool for addressing some of the most fundamental question
about the nature of T&P
- Where does extraversion come from?
-
The Premise
We are pretty ignorant about the biology linking genotypes to phenotypes
(e.g., N, E, and SC). So its difficult to generate good hypotheses (candidate
genes to examine).
If we could somehow harness genetics to understand the molecular
neurobiology of T&P and associated psychiatric disorders, it would enable us
to:
-
Redefine diagnostic categories and T&P traits in terms of quantifiable etiology (root
causes)
Develop novel treatments or prevention efforts targeting links in the etiological chain
Predict treatment response or more quickly pick the best treatment (e.g., carriers of a
particular polymorphism).personalized or precision medicine
Enhance prognosis: You (and other carriers of SNP X) have 3 months to live
Provide a novel discovery tool for addressing some of the most fundamental question
about the nature of T&P
- Where does extraversion come from?
-
1 inch = 25.4 mm =
6.4 allelic variants
t surprisingly, they lacked the power to detect a single genetic variant that was
gnificantly associated with differences in N/NE or E/PE
t surprisingly, they lacked the power to detect a single genetic variant that was
gnificantly associated with differences in N/NE or E/PE
t surprisingly, they lacked the power to detect a single genetic variant that was
gnificantly associated with differences in N/NE or E/PE after correcting for
ultiple comparisons
t surprisingly, they lacked the power to detect a single genetic variant that was
gnificantly associated with differences in N/NE or E/PE after correcting for
ultiple comparisons
Meyer et al Amer
Meyer et al Amer
ase of Asprin
w
ecial meeting held December 18, 1987, it was decided to end prematurely a ran
blind experiment (n=22l) on the effects of aspirin on reducing heart attacks. The
unusual termination of this experiment was that it had become so clear that asp
ted heart attacks (and deaths from heart attacks) that it would be unethical to c
half the subjects a placebo. Now what do you suppose was the magnitude of the
mental effect that was so dramatic as to call for the termination of this research?
wald
as a significant (P<0.00001) reduction [from 2.16% to 1.27%] in the risk of hear
those in the aspirin group. Applying the studys estimated risk reduction of 44%
.S. Census estimate of about 46 million male U.S. residents 50 or older, regular s
of aspirin should prevent approximately 420,000 heart attacks during a 5-year pe
mer Psychol 1990; Greenwald et al JPSP in press; but see also Ferguson Rev Gen Psychol 2009
ase of Asprin
w
ecial meeting held December 18, 1987, it was decided to end prematurely a ran
blind experiment (n=22l) on the effects of aspirin on reducing heart attacks. The
unusual termination of this experiment was that it had become so clear that asp
ted heart attacks (and deaths from heart attacks) that it would be unethical to c
half the subjects a placebo. Now what do you suppose was the magnitude of the
mental effect that was so dramatic as to call for the termination of this research?
wald
as a significant (P<0.00001) reduction [from 2.16% to 1.27%] in the risk of hear
those in the aspirin group. Applying the studys estimated risk reduction of 44%
.S. Census estimate of about 46 million male U.S. residents 50 or older, regular s
of aspirin should prevent approximately 420,000 heart attacks during a 5-year pe
mer Psychol 1990; Greenwald et al JPSP in press; but see also Ferguson Rev Gen Psychol 2009
ase of Asprin
w
ecial meeting held December 18, 1987, it was decided to end prematurely a ran
blind experiment (n=22l) on the effects of aspirin on reducing heart attacks. The
unusual termination of this experiment was that it had become so clear that asp
ted heart attacks (and deaths from heart attacks) that it would be unethical to c
half the subjects a placebo. Now what do you suppose was the magnitude of the
mental effect that was so dramatic as to call for the termination of this research?
wald
as a significant (P<0.00001) reduction [from 2.16% to 1.27%] in the risk of hear
those in the aspirin group. Applying the studys estimated risk reduction of 44%
.S. Census estimate of about 46 million male U.S. residents 50 or older, regular s
of aspirin should prevent approximately 420,000 heart attacks during a 5-year pe
mer Psychol 1990; Greenwald et al JPSP in press; but see also Ferguson Rev Gen Psychol 2009
me Point
ects can be very practically important when they are cumulated over m
mer Psychol 1990; Greenwald et al JPSP in press; but see also Ferguson Rev Gen Psychol 2009
- $250M
- 1-2 stealth fighter jets
- Much less than a single navy submarine
- Fraction of the ~$9 billion cost of the LargeVisscher
et al 2012
Hadron
- $250M
- 1-2 stealth fighter jets
- Much less than a single navy submarine
- Fraction of the ~$9 billion cost of the Large Hadron
Visscher et al 2012
Collider
- $250M
- 1-2 stealth fighter jets
- Much less than a single navy submarine
- Fraction of the ~$9 billion cost of the Large Hadron
Visscher et al 2012
Collider
- $250M
- 1-2 stealth fighter jets
- Much less than a single navy submarine
- Fraction of the ~$9 billion cost of the Large Hadron
Visscher et al 2012
Collider
- $250M
- 1-2 stealth fighter jets
- Much less than a single navy submarine
- Fraction of the ~$9 billion cost of the Large Hadron
Visscher et al 2012
Collider
Perhaps a different
strategy would be helpful?
G-E Interactions (G x E)
- Traits cluster in families (remember Draco Malfoy)
G-E Interactions (G x E)
- Traits cluster in families (remember Draco Malfoy)
G-E Interactions (G x E)
- Traits cluster in families (remember Draco Malfoy)
G-E Interactions (G x E)
- Traits cluster in families (remember Draco Malfoy)
G-E Interactions (G x E)
Family Conflict: Individuals who are genetically predisposed)to low C/SC are even more
impulsive in a conflictual family environment;
(a) trigger,
(b) compensate for, or
(c) enhance genetic predisposition
Family Conflict: Individuals who are genetically predisposed)to low C/SC are even more
impulsive in a conflictual family environment;
(a) trigger,
(b) compensate for, or
(c) enhance genetic predisposition
Family Conflict: Individuals who are genetically predisposed)to low C/SC are even more
impulsive in a conflictual family environment;
(a) trigger,
(b) compensate for, or
(c) enhance genetic predisposition
Family Conflict: Individuals who are genetically predisposed)to low C/SC are even more
impulsive in a conflictual family environment;
(a) trigger,
(b) compensate for, or
(c) enhance genetic predisposition
Family Conflict: Individuals who are genetically predisposed)to low C/SC are even more
impulsive in a conflictual family environment;
(a) trigger,
(b) compensate for, or
(c) enhance
particular genetic predispositions
A Famous Illustration
monoamine oxidase A
A Famous Illustration
monoamine oxidase A
A Famous Illustration
Caspi (Duke)
Caspi (Duke)
Caspi (Duke)
Caspi (Duke)
Short
Long
To be continued
Traits (Evildoing)
Continued
1.
2.
Continued
1.
2.
Continued
1.
2.
Continued
1.
2.
Continued
Continued
Continued
Continued
Continued
Continued
Continued
Continued
The gap between science, the media (NY Times/Scientific American), and the
public. What gets lost in translation?
Continued
The gap between science, the media (NY Times/Scientific American), and the
public. What gets lost in translation?
Continued
Time-Permitting
Review Questions
T&P reflect
A. Nature
B. Nurture
C. Both
Nature (heritability) is
A. Fixed and
immutable
B. Plastic and can
change in
response to
growing
autonomy or
due to
cumulative
impact
Heritability is
A. The proportion
of variation in a
trait, such as
C/SC, that is
accounted for by
the pedigree
(family tree)
B. PV/GV
C. A and B
Estimates of heritability
A. Are fixed
B. Can be influenced by
social and
environmental
influences (e.g., living
in a conservative
religious community)
that increase or
decrease the amount
of variation in the trait
(e.g., disinhibition,
partying, smoking)
Heritability
A. Is the % of
variation in a trait,
such as E/PE, that
is passed down
from your parents
B. Reflects the
inheritance of
genes, not
phenotypes or
traits
Heritability describes
A. The % of my trait that
is inherited (nature)
vs. environmental
(nurture)
B. The % of phenotypic
variation across a
group of individuals
that is influenced by
genetic factors
C. Individuals within a
population (e.g., Alex)
The End
Extra Slides
Traits (Evildoing)
Bogdan (Wash U)
he Problem of Assumptions
Kalin (UW)
The environment (e.g., learning, stress) can alter gene expression (protein synthesis)
without altering the genome (DNA; hence, not heritable)
Epigenetic mechanisms involve changes to how readily transcription factor can access
the DNA
E.g., methylation: addition of a methyl group onto a cytosine (1 of the 4 base
pairs that make up DNA) silences the gene because methyl hinders the
transcription factors
-
Epigenetic modifications of the genome have long been known to exist e.g., all cells in
the body share the same DNA; accordingly, there must be a mechanism whereby
different genes are active in liver cells vs. neurons
Work in rodents by Michael Meaneys group demonstrates that maternal behavior can
influence the adult T&P of offspring and that this is epigenetic dependent
The environment (e.g., learning, stress) can alter gene expression (protein synthesis)
without altering the genome (DNA; hence, not heritable)
Epigenetic mechanisms involve changes to how readily transcription factor can access
the DNA
E.g., methylation: addition of a methyl group onto a cytosine (1 of the 4 base
pairs that make up DNA) silences the gene because methyl hinders the
transcription factors
-
Epigenetic modifications of the genome have long been known to exist e.g., all cells in
the body share the same DNA; accordingly, there must be a mechanism whereby
different genes are active in liver cells vs. neurons
Work in rodents by Michael Meaneys group demonstrates that maternal behavior (xfostered) can influence the adult T&P of offspring and that this is epigenetic dependent
The environment (e.g., learning, stress) can alter gene expression (protein synthesis)
without altering the genome (DNA; hence, not heritable)
Epigenetic mechanisms involve changes to how readily transcription factor can access
the DNA
E.g., methylation: addition of a methyl group onto a cytosine (1 of the 4 base
pairs that make up DNA) silences the gene because methyl hinders the
transcription factors
-
Epigenetic modifications of the genome have long been known to exist e.g., all cells in
the body share the same DNA; accordingly, there must be a mechanism whereby
different genes are active in liver cells vs. neurons
Elegant mechanistic work in rodents by Michael Meaneys group demonstrates that one
aspect of the early environment , maternal behavior (x-fostered), can influence the T&P
of offspring and that this is epigenetic dependent
This is exceedingly hard to study in humans because epigenetic mechanisms vary across
the brain and body, so measuring epigenetic effects in blood or saliva may not tell you
AJ Shackman
9 December 2013
Students?
Lemery (ASU)
Jaffee (Penn)
E.g., the reason children who are spanked or smacked are more aggressive than
children who are not may be that parents and kids share a genetic risk for
aggressive behavior (common cause)
E.g., the reason children who are spanked or smacked are more aggressive than
children who are not may be that parents and kids share a genetic risk for
aggressive behavior (common cause)
E.g., the reason children who are spanked or smacked are more aggressive than
children who are not may be that parents and kids share a genetic risk for
aggressive behavior (common cause)
E.g., the reason children who are spanked or smacked are more aggressive than
children who are not may be that parents and kids share a genetic risk for
aggressive behavior (common cause)
E.g., individuals predisposed to high E/PE seeking may be more prone to attend
parties, go to bars, meet new people, be exposed to delinquent peers, and try
peer relationships, negative life events such as divorce and exposure to trauma
Environments are heritable because genotype influences behaviors that evoke,
select, and modify features of the environment
- Environments less amenable to behavioral modification are less heritable, e.g., the
death of a loved one, losing ones home in a natural disaster
- Than those that depend on the individuals behavior, e.g., divorce, getting fired
Take home: Genetic risk factors do not necessarily have direct effects on phenotypes (T&P,
Dx), but can work indirectly by modifying sensitivity to environmental risk factors (active GE) or by influencing exposure
to risk (passive, evocative G-E)
peer relationships, negative life events such as divorce and exposure to trauma
Environments are heritable because genotype influences behaviors that evoke,
select, and modify features of the environment
- Environments less amenable to behavioral modification are less heritable, e.g., the
death of a loved one, losing ones home in a natural disaster
- Than those that depend on the individuals behavior, e.g., divorce, getting fired
Take home: Genetic risk factors do not necessarily have direct effects on phenotypes (T&P,
Dx), but can work indirectly by modifying sensitivity to environmental risk factors (active GE) or by influencing exposure
to risk (passive, evocative G-E)
Translational Promise
Sara argues that, in principle, if one could identify with high sensitivity and
specificity at-risk G-E pairs
- At-risk kids paired with risky environments (parental style, peers, adversity, abuse,
etc.)
You could target them for precision interventions BEFORE the onset of cumulative
damage
- in effect, she argues for a more nuanced extension of the Moffitt PNAS strategy
- instead of identifying kids with low C/SC
- identify kids with low C/SC and other environmental risk factors
- this is akin, as I understand it, to what Andreas lab does (ADHD kid + parent with
sub-optimal skill)
- potentially, one could use biomarkers (gene screens) to identify high-risk parent-kid
dyads
Bogdan (Wash U)
Goldsmith Slides
The genome
3.1-3.2
billion bases
~21-23,000
genes
ATTGTTATCCGCTCACAATTCCACACAAT
6 repeat units
CACACACACACACACACACACACACACACACACACAGAGTGAGCTAACTCACATTAATTGCGTTGC
ATTGTTATCCGCTCACAATTCCACACAAT
9 repeat units
frequently found within the genome
highly polymorphic
21 rare alleles
3 common alleles
Out of Africa
Gene
Identification
Where to look
Targeted
Linkage or Cytogenetic Positional
candidate
Pathophysiology Candidate gene
Animal models
Genome-wide
How to look
A. Linkage analysis
B. Association Studies
A. Linkage our
experience with linkage so
far in this course
An intuitive example of
linkage analysis for a
polygenic trait
- The affected sib pair
method, (analyzing
allele sharing)
Sample, disorder, set of markers
Linkage Analysis:
formal definition
Statistical procedure for analyzing
within-family associations between
genetic markers and disease
phenotypes that takes into account
the complications of reduced
penetrance and crossing-over.
Test statistic = lod score
Lod Scores
Lod Score
-3
1:1000
-2
1:100
-1
1:10
10:1
100:1
1000:1
Genome-Wide Linkage
Analysis
Targeted Linkage Approach
Depends on fortuitous
observations
Genome-Wide linkage
Approach
Need a marker AT LEAST every ~
10cM 300-400 markers
Disadvantages
Requires family-study design
Good for genes of large effect; low power to
detect genes accounting for 5% or less of
variance
Limited resolution: tight linkage can be
millions of bases away
Does not find the gene, rather identifies a
B. Allelic Association
Association between allele status
and phenotype in unrelated
individuals. Population-level
association
OR = 60*60 = 2.25
40*40
Not O
(A,B,AB)
O
Stomach Cancer
60
40
40
60
2-26-1986
11-10-1988
4-18-1990
7-16-1993
10-22-1993
1-02-1996
2-26-1986
1-13-1993
11-10-1988
11-07-1989
4-18-1990
7-16-1993
4-23-1999
10-22-1993
2-14-1992
1-02-1996
11-01-1996
Allelic Association
Advantages
Easy design to implement
Compares cases versus controls
In principle, very high statistical power
In principle, can identify causal agent
Disadvantages
Need to know functional polymorphisms
in a candidate gene (for direct
association)
Concern about false-positives due to
mis-matching cases and controls
(stratification bias next slide)
+
Hyper
24
(.40)
16
(.40)
40
(.40
)
Not
O
36
24
60
60
40
100
+
Hyper
24
(.40)
16
(.40)
40
(.40
)
Not
O
36
24
60
60
40
100
Hyper
+
Hyper
9
(.10)
1
(.10)
10
(.1
0)
No
t
O
81
90
90
10
100
+
Hyper
24
(.40)
16
(.40)
40
(.40
)
Not
O
36
24
60
60
40
100
Combined:
OR = 1.83
Hyper
+
Hyper
9
(.10)
1
(.10)
10
(.1
0)
Not
O
81
90
90
10
100
Hyper
+
Hyper
33
(.22)
17
(.34)
50
(.25
)
Not
O
117
33
150
Original
OR=8.7
Original
OR=8.7
Winners Curse
Cumulative Odds Ratio as a Function of
Publication Year
Original
OR=8.7
Final OR=1.4
Ethnic mismatching
Winners Curse
Gene-environment Interaction
G effect may only exist in certain
environments
(reminder: heritability estimates are
Ethnic mismatching
Winners Curse
Gene-environment Interaction
Effect may only exist in certain
environments
APOE
Polymorphism
D
Assess relationship of D locus
to phenotype directly
expect D to be a functional
polymorphism in a candidate gene
Indirect Association
M1 M D M3
2
Haplotypes
Haplotype is a generalization of the
concept of a single genotype to
multiple linked loci refers to a
series of markers (usually SNPs)
Haplotypes
Haplotype is a generalization of the
concept of genotype to multiple loci
Recombination is not random, but rather
tends to occur at hot spots
This gives rise to blocks of DNA
(haplotypes), where there is very little
recombination within blocks but extensive
recombination between blocks
STOPPED HERE
Haplotypes
A
3 Genotypes:
AT at locus 1
CG at locus 2
GC at locus 3
Haplotypes
(alleles inherited
together on a
segment of the
same
chromosome)
ACG & TGC
Haplotype Blocks
rdon & Abecasis (2003). Using haplotype blocks to map the human geno
ends in Genetics, 19: 135-140.
rdon & Abecasis (2003). Using haplotype blocks to map the human geno
ends in Genetics, 19: 135-140.
Out of Africa
Empirical Evidence
Study
Original
N
Weedon (2007)
4,921
Sanna (2008)
6,669
28,801
1 variant
Weedon (2008)
13,655
16,482
Gudbjartsson
(2008)
Lettre (2008)
29,820
8,541
15,821
> 10,000
20
variants
27
variants
12
variants
The raw estimate that this produces is that 45% of the total
variation for height (and hence 56% of the heritability) in the
Brisbane cohort can be explained by common SNPs (regardless
of their significance).
By accounting for imperfect linkage disequilibrium between
tagging and causal variants, Yang et al. up their estimate of
common variant effects from 56% to at least 67% of the genetic
contribution to height.
A further correction assumes that causal variants are likely to be
deleterious and hence at lower frequency than tagging SNPs,
and in this case leads to the conclusion that most of the
heritability for height can be captured by common variants.
Median =
1.33
GWAS of Behavioral
Traits
Design:
~3300 Sz and 3600
Controls
1M SNP markers
Results:
Most highly associated
SNP
had p = 3.4 x 10-7
Second most highly
http://www.genome.gov/GWAStudies/index.cfm?pageid=26525384#searchForm
If heterogeneity is
common,
Then, rare variants (which would
be population specific) might
explain part of the heritability not
explained by common variants.
Recurrent CNVs
Conclusions: Gene
Identification
Common Disease, Common Variant:
Can now do genome-wide studies
Effect of any variant will be very small
Require large samples, consortia & metaanalysis
Clinical implications uncertain
Type of
Association
Interpretation
Genome-wide
Resolution
Preferred Sample
Sensitivity
Specificity
Linkage
Allelic
Association
(Direct)
w/i Family
between
marker and
phenotype
Linkage
Disequilibrium
(Indirect)
Pop assoc btw
marker and
phenotype
Allelic
Association
(Direct)
Linkage
Disequilibrium
(Indirect)
Within family
between
marker and
phenotype
Region
implicated
Gene or nearby
gene
implicated
Region
implicated
Linkage
Type of Association
Interpretation
Genome-wide
Resolution
Preferred Sample
Sensitivity
Specificity
Linkage
Disequilibrium
(Indirect)
Linkage
Allelic Association
(Direct)
Type of Association
Interpretation
Region implicated
Region implicated
No, maybe in
the future
(~60,000)
Now feasible
(~500,000,
HapMap)
Genome-wide
approach?
Resolution
Preferred Sample
Sensitivity
Specificity
Yes, 300-400
markers
Linkage
Disequilibrium
(Indirect)
Linkage
Allelic Association
(Direct)
Type of Association
Interpretation
Region implicated
Region implicated
Genome-wide
Now feasible
(~500,000, HapMap)
Resolution
Preferred Sample
Sensitivity
Specificity
Not relevant
Typically
<< 1
centimorgan
Linkage
Disequilibrium
(Indirect)
Linkage
Allelic Association
(Direct)
Type of Association
Interpretation
Region implicated
Region implicated
Genome-wide
Now feasible
(~500,000, HapMap)
Resolution
Not relevant
Unrelated
individuals
Genetic isolates
if rare
Preferred
Sample
Sensitivity
Specificity
Large pedigrees
Sib pairs
Linkage
Disequilibrium
(Indirect)
Linkage
Allelic Association
(Direct)
Type of Association
Interpretation
Region implicated
Region implicated
Genome-wide
Now feasible
(~500,000, HapMap)
Resolution
Not relevant
Preferred Sample
Large pedigrees
Sib pairs
Unrelated
individuals
Genetic isolates
if rare
Sensitivity
Relatively low
Relatively High
Relatively High
Specificity
Linkage
Disequilibrium
(Indirect)
Linkage
Allelic Association
(Direct)
Type of Association
Interpretation
Region implicated
Region implicated
Genome-wide
Now feasible
(~500,000, HapMap)
Resolution
Not relevant
Preferred Sample
Large pedigrees
Sib pairs
Unrelated
individuals
Genetic isolates
if rare
Sensitivity
Relatively low
Relatively High
Relatively High
Specificity
Relatively High
Relatively Low
Relatively High
(?)
END OF PRESENTATION
Yes, from the floor it looked as though Dans head would touch the ceiling
Anx & Dep Assoc of America Annual Meeting 2014
Conceptual Roadmap
Individual differences in T&P reflect the brain
e.g., Individuals with higher levels of N/NE
show enhanced activation and slower recovery
in the amygdala
Where do differences in brain activation
come from?
We cant assay tissue from the amygdala in
people, but can we use the genome (DNA) to
identify candidate mechanisms that could be
mechanistically tested in animals?
Students
Charles Darwin