Functional Neuroimaging of Genetically
Driven Variation in Brain Function:
Towards a Biological Understanding of
Individual Differences in Behavior
Ahmad R. Hariri, Ph.D.
Developmental Imaging Genomics Program
Department of Psychiatry
University of Pittsburgh School of Medicine
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
How do we get from here to there?
Behavior:
complex functional
interactions and
emergent
phenomena
Genes:
multiple
susceptibility
alleles each of
small effect
The path from here to there…
IMAGING GENOMICS
Behavior:
complex functional
interactions and
emergent
phenomena
Genes:
multiple
susceptibility
alleles each of
small effect
Cells:
Subtle
molecular
alterations
Systems:
response bias to
environmental
cues
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
Central serotonergic system
Slide 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)
Figure courtesy of K.P. Lesch
The 5-HTTLPR
Harm avoidance,
Neuroticism,
Depression,
Anxiety
Genes:
Short and long
allele variants
Cells:
Alterations in
synaptic 5-HT
5-HTTLPR and temperament
IMAGING GENOMICS
Harm avoidance,
Neuroticism,
Depression,
Anxiety
Genes:
Short and long
allele variants
Cells:
Alterations in
synaptic 5-HT
Systems:
amygdala bias to
environmental cues
The Amygdala
fMRI amygdala reactivity paradigm
(A.K.A. Hariri’s Hammer)
5-HTTLPR S allele driven amygdala
hyper-reactivity to environmental cues
P < 0.05, corrected
Hariri et al., Science 2002
S allele driven amygdala hyper-reactivity
Berlin replication in healthy adults
R=0.6, p<0.005
LL
LS
SS
Heinz et al., Nature Neuroscience 2005
Italian replication in healthy adults
S carriers > L/L
% Signal Change in Amygdala
0,30
0,25
0,20
0,15
0,10
0,05
0,00
ss
ls
ll
SERT genotype
P < 0.05, corrected
Bertolino et al., Biological Psychiatry 2005
Pittsburgh replication in healthy adults
5-HTTLPR S carrier > LL
(P < 0.05, uncorrected)
Sample Demographics:
LL: 8♀/4♂; Mean age = 46.1
S carrier: 9♀/7♂; Mean age 47.5
Swedish replication in social phobics
Furmark et al., Neuroscience Letters 2004
Mean +/- 1 SEM Right Amygdala BOLD
NIMH replication in healthy adults
N = 92
.3
.2
.1
0.0
-.1
N=
27
65
L/L
S Carrier
5-HTTLPR
Hariri et al., Archives (2005)
Elaboration: S allele load and sex effects
.3
.2
.1
SEX
0.0
Female
-.1
N=
Male
14
13
L/L
28
23
L/S
5
9
S/S
5-HTTLPR
Hariri et al., Archives (2005)
5-HTTLPR and temperament
IMAGING GENOMICS
?????????
Genes:
Short allele
variant
Cells:
Increased
synaptic 5-HT
Systems:
amygdala bias to
environmental cues
Amygdala reactivity and harm avoidance
30
20
20
Total Harm Avoidance
30
10
10
0
0
-10
-.6
-.4
-.2
-.0
.2
Left Amygdala BOLD
.4
.6
.8
-10
-.8
-.6
-.4
-.2
0.0
.2
.4
.6
Right Amygdala BOLD
* No correlation between amygdala reactivity and HA
.8
Prefrontal-Amygdala Dynamics
Wood & Grafman 2003
Reduced functional coupling of the amygdala and
prefrontal cortex in S allele carriers
Overall Coupling
5-HTTLPR Effects
left
right
Pezawas et al. Nature Neuroscience 2005
Amygdala-Prefrontal connectivity predicts HA
Functional circuitry is key for understanding
complex emergent phenomena
5-HTTLPR biases corticolimbic information
processing related to temperament
Hamann Nature Neuroscience 2005
Subgenual PFC 5-HT1A and 5-HT2A binding
predict amygdala reactivity
sgPFC 1A/2A ratio predicts amygdala reactivity
DRN 5-HT1A predicts amygdala reactivity
Typical 5-HT neuron and target synapse
Figure courtesy of K.P. Lesch
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
Right amygdala activity
(in arbitrary units)
2.00
1.00
0.00
-1.00
T carriers > G/G
G/G
T carrier
hTPH2 genotype
Brown et al., Molecular Psychiatry (in press)
hTPH2 G(-844)T biases amygdala reactivity
Emotional
Behaviors?
Genes:
hTPH2
expression?
Cells:
5-HT synthesis?
Systems:
amygdala bias to
environmental cues
Acknowledgments
"
"
University of Pittsburgh
Steve Manuck
Bob Ferrell
Carolyn Meltzer
Sarah Brown
Patrick Fisher
Scott Kurdilla
NIMH - GeCaP
Danny Weinberger
Emily Drabant
Karen Munoz
Anand Mattay
Lukas Pezawas
Andreas Meyer-Lindenberg
Support:
NIMH P01MH041712-18, R24MH067346-03, R01MH061596-04; NIDA R01DA018910-01; NARSAD