Ahmad R. Hariri, Ph.D. Developmental Imaging Genomics Program Department of Psychiatry
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Transcript of Ahmad R. Hariri, Ph.D. Developmental Imaging Genomics Program Department of Psychiatry
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
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ss ls ll
SERT genotype
% S
ign
al C
han
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myg
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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
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-10
Left Amygdala BOLD
.8.6.4.2-.0-.2-.4-.6
Tot
al H
arm
Avo
idan
ce
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-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
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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
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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