Ahmad R. Hariri, Ph.D. Developmental Imaging Genomics Program Department of Psychiatry University of...

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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

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

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

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

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

ss ls ll

SERT genotype

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

N = 92

Hariri et al., Archives (2005)

Elaboration: S allele load and sex effects

92313 52814N =

5-HTTLPR

S/SL/SL/L

Female

Hariri et al., Archives (2005)

5-HTTLPR and temperament

Genes:Short allele

variant

Cells:Increased

synaptic 5-HT

?????????

environmental cues

Amygdala reactivity and harm avoidance

Right Amygdala BOLD

.8.6.4.20.0-.2-.4-.6-.8

Left Amygdala BOLD

.8.6.4.2-.0-.2-.4-.6

* 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

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

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

hTPH2 genotypeG/G T carrier

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?

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

Ahmad R. Hariri, Ph.D. Developmental Imaging Genomics Program Department of Psychiatry University of...

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