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Ahmad R. Hariri, Ph.D.
Developmental Imaging Genomics Program
Department of Psychiatry
University of Pittsburgh School of Medicine
Functional Neuroimaging of Genetically Driven Variation in Brain Function:
Towards a Biological Understanding of Individual Differences in Behavior
Why study genes?
• Various aspects of cognition, temperament, and personality are highly heritable (40-70%)
• Account for the lionshare of susceptibility to major psychiatric disorders
• Transcend phenomenological diagnosis, and represent mechanisms of disease
• Offer the potential to identify at-risk individuals and biological pathways for the development of new treatments
Deshaies 02 — DNA Man #1
Genes:multiple
susceptibility alleles each of
small effect
Behavior:complex functional
interactions and emergent
phenomena
How do we get from here to there?
Genes:multiple
susceptibility alleles each of
small effect
The path from here to there…
Cells:Subtle
molecular alterations
Behavior:complex functional
interactions and emergent
phenomena
Systems:response bias to
environmental cues
IMAGING GENOMICSIMAGING GENOMICS
Imaging Genomics:Basic Principles
Imaging Genomics: Basic Principles
1) Selection of candidate genes
– Well defined functional polymorphisms, associated with specific physiological effects at the cellular level in distinct brain circuits
– Genes with identified SNPs or other allele variants with likely functional implications involving circumscribed neuroanatomical systems
Imaging Genomics: Basic Principles
2) Control for non-genetic factors– Systematic differences between genotype groups could
either obscure a true gene effect or masquerade for one
• Age, gender, IQ, population stratification
• Environmental factors such as illness, injury, or substance abuse
• Task performance– Linked pari passu with BOLD response– Match or consider variability
Imaging Genomics: Basic Principles
3) Task selection– Imaging tasks must maximize sensitivity and
inferential value, as the interpretation of potential gene effects depends on the validity of the information processing paradigm
• Engage circumscribed brain circuits
• Produce robust signals in all subjects
• Show variance across subjects
Imaging Genomics: Applications
Slide courtesy of K.P. Lesch
Central serotonergic system
Figure courtesy of K.P. Lesch
Typical 5-HT neuron and target synapse
Figure courtesy of K.P. Lesch
5-HT Transporter Promoter Variant (5-HTTLPR)
The 5-HTTLPR
Genes:Short and long allele variants
Cells:Alterations in synaptic 5-HT
Harm avoidance,Neuroticism, Depression,
Anxiety
5-HTTLPR and temperament
Genes:Short and long allele variants
Cells:Alterations in synaptic 5-HT
Harm avoidance,Neuroticism,Depression,
Anxiety
Systems:amygdala bias to
environmental cues
IMAGING GENOMICSIMAGING GENOMICS
The Amygdala
fMRI amygdala reactivity paradigm
(A.K.A. Hariri’s Hammer)
P < 0.05, corrected
5-HTTLPR S allele driven amygdalahyper-reactivity to environmental cues
Hariri et al., Science 2002
S allele driven amygdala hyper-reactivity
Heinz et al., Nature Neuroscience 2005
Berlin replication in healthy adults
LL LS SS
R=0.6, p<0.005
Bertolino et al., Biological Psychiatry 2005
Italian replication in healthy adults
0,00
0,05
0,10
0,15
0,20
0,25
0,30
ss ls ll
SERT genotype
% S
ign
al C
han
ge
in A
myg
dal
a
P < 0.05, corrected
S carriers > L/L
Pittsburgh replication in healthy adults
5-HTTLPR S carrier > LL(P < 0.05, uncorrected)
Sample Demographics:LL: 8♀/4♂; Mean age = 46.1S carrier: 9♀/7♂; Mean age 47.5
Furmark et al., Neuroscience Letters 2004
Swedish replication in social phobics
NIMH replication in healthy adults
6527N =
5-HTTLPR
S CarrierL/LM
ea
n +
/- 1
SE
M R
igh
t Am
ygd
ala
BO
LD .3
.2
.1
0.0
-.1
N = 92
Hariri et al., Archives (2005)
Elaboration: S allele load and sex effects
92313 52814N =
5-HTTLPR
S/SL/SL/L
Mea
n +
/- 1
SE
M R
ight
Am
ygda
la B
OLD
.3
.2
.1
0.0
-.1
SEX
Female
Male
Hariri et al., Archives (2005)
5-HTTLPR and temperament
Genes:Short allele
variant
Cells:Increased
synaptic 5-HT
?????????
Systems:amygdala bias to
environmental cues
IMAGING GENOMICSIMAGING GENOMICS
Amygdala reactivity and harm avoidance
Right Amygdala BOLD
.8.6.4.20.0-.2-.4-.6-.8
Tot
al H
arm
Avo
idan
ce
30
20
10
0
-10
Left Amygdala BOLD
.8.6.4.2-.0-.2-.4-.6
Tot
al H
arm
Avo
idan
ce
30
20
10
0
-10
* No correlation between amygdala reactivity and HA
Prefrontal-Amygdala Dynamics
Wood & Grafman 2003
Reduced functional coupling of the amygdala and prefrontal cortex in S allele carriers
Pezawas et al. Nature Neuroscience 2005
right
left
Overall Coupling 5-HTTLPR Effects
Amygdala-Prefrontal connectivity predicts HA
Functional circuitry is key for understanding complex emergent phenomena
Hamann Nature Neuroscience 2005
5-HTTLPR biases corticolimbic information processing related to temperament
Subgenual PFC 5-HT1A and 5-HT2A binding predict amygdala reactivity
sgPFC 1A/2A ratio predicts amygdala reactivity
DRN 5-HT1A predicts amygdala reactivity
Figure courtesy of K.P. Lesch
Typical 5-HT neuron and target synapse
hTPH2 G(-844)T polymorphism
• Relatively high minor allele frequency (T allele = 38%)
• Located within 1 Kb (844 bp upstream) of the transcription initiation site of hTPH2 and is likely a constituent of the proximal promoter of the gene
• Regulatory variants often produce functional changes in gene expression
• Transcriptional regulatory databases indicate transcription factor recognition sequence homology surrounding the -844 promoter variant (http://www.genomatix.de)
• In silico evidence that the G to T allele substitution potentially modifies the binding of several transcription factors including octamer-binding factor 6, special AT-rich sequence-binding protein 1 as well as homeodomain proteins MSX-1 and MSX-2
hTPH2 G(-844)T biases amygdala reactivity
-1.00
0.00
1.00
2.00
hTPH2 genotypeG/G T carrier
Rig
ht
amyg
dal
a ac
tivi
ty
(in
arb
itra
ry u
nit
s)T carriers > G/G
Brown et al., Molecular Psychiatry (in press)
hTPH2 G(-844)T biases amygdala reactivity
Genes:hTPH2
expression?
Cells:5-HT synthesis?
EmotionalBehaviors?
Systems:amygdala bias to
environmental cues
"
"
Acknowledgments
University of PittsburghSteve Manuck
Bob FerrellCarolyn Meltzer
Sarah BrownPatrick FisherScott Kurdilla
NIMH - GeCaPDanny Weinberger
Emily DrabantKaren MunozAnand Mattay
Lukas PezawasAndreas Meyer-Lindenberg
Support:NIMH P01MH041712-18, R24MH067346-03, R01MH061596-04; NIDA R01DA018910-01; NARSAD