imaging genetic pathwaystranslational research strategy

John A. Fossellawww.slideshare.net/johnfossella

THE goal:“biomarker-driven healthcare”“commoditized technology”“open source, low-cost services”

OUR goal:“biomarker links to cognitive processes that play a role in the origins and intervention of mental illness”

MAOANRG1DRD4DAT1etc.

“xeno-phenocopy” validity problem

in translational research

MAOANRG1DRD4DAT1etc.

MAOANRG1DRD4DAT1etc.

MAOANRG1DRD4DAT1etc.

Is the population of planet Earthlarge enough to minimize type I & type II error ?

“Millions” x “thousands” x “hundreds”(genetic variants) (voxels) (task contrasts)

relevance to many disorderspost-natal developmental trajectory

well studied anatomicallywell studied pharmacologically

relevance to cognitive interventions that have long-term benefits

TASK… VALIDITY - parsing cognition

ATTENTION as a model system

Psychopathology

Anterior Cingulate Cortex

Attention

+ *

+

+

+

+

D1= 400-1600 ms

400 ms

RT < 1700 ms

3500 - RT - D1 ms

100 ms

cue

target

Human Attention Network Task (ANT)

TASK …

Distribution of normalized scores for executive attention

N = 200 normal adult volunteers

Stimulus-Response conflict score

0

10

20

30

40

50

60

70

80

90

0.05

0.15

0.25

0.35

This group“Slows down”duringincongruent trials

TASK … RELIABILITY is there sufficient or too much variation ?

TASK … VALIDITY - where in the assay does the inter-subject variability originate ?

Where is the variation coming from ?

baseline reaction times ?perceptual differences ?

differences in motivation ?paying attention to errors ?

+ *

+

+

+

+

D1= 400-1600 ms

400 ms

RT < 1700 ms

3500 - RT - D1 ms

100 ms

cue

target

• Alerting network• Orienting network• Executive control network

• Alerting network• Orienting network• Executive control network

CANDIDATE GENE … anatomical & pharmacological constraints

Fan et al., 2004

 Correlation values between twin pairs of MZ and DZ twins for each network and mean RT._______________________________________Twin Alerting Orienting Conflict RT_______________________________________MZ .465* .099 .727** .740**

DZ .375 .395* .281 .659**

_______________________________________Note: * p < .05; ** p < .01

Heritability Alerting OrientingConflict RT_____________________________________________h2

F = 2 (rMZ – r DZ) .18 -.59 .89 .16

h2H = (rMZ – r DZ)/ .14 -.49 .62 .24

(1 – r DZ)

ML fit:h2 .18 .00 .72 .16

TASK … HERITABILITY

Dopamine Transporter

Dopamine Receptor

Monoamine Oxidase A

COMT

CANDIDATE GENE … selection of polymorphism … known SYNAPTIC function ?

CANDIDATE GENE … polymorphism … frequency … patterns of LD ?

STR Y-chr LOCUS #DYS393 14DYS19 14DYS391 10DYS439 10DYS389-1 12DYS389-2 17DYS388 12DYS390 22DYS426 11DYS385a 15DYS385b 16DYS392 11

HAPLOTYPE “G”Saudi Arabia, Iraq, Iran, Pakistan

INTERPRETATION… internally & externally consistent with literature ?

Low DA levels High DA levels

2030N =

VAR00002

2.001.00

Me

an

+-

1 S

E V

AR

000

01

.24

.22

.20

.18

.16

.14

.12Co

nfli

ct r

atio

sco

re

COMT Val 108/158MAOA long prom. repeat

COMT Met 108/158MAOA short prom. repeat

MAOA (4-repeat) – (3-repeat)

4-repeat, LOW MA

3-repeat, Hi MA

Re

ac

tio

n T

ime

Dif

f

Red = activity biased by MAOA 4-repeat allele

Blue = activity biased by MAOA 3-repeat allele

INTERPRETATION … internal & external robustness

Fan et al., 2003

INTERPRETATION … is the inter-subject variation coming from a meaningful source ?

-0.5

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

Congruent Incongruent

Condition

Sig

na

l c

ha

ng

e (

%)

A1/A1, A1/A2

A2/A2

DRD2 TaqA1 allele

Fossella et al., 2006

CANDIDATE GENE … anatomy & pharmacology constraints

Striatal activation is significantly increased for subjects

carrying the 9R-allele of the DAT1-VNTR, whereas cerebellar vermis activation

is significantly attenuated.

Durston et al., 2006

DEVELOPMENTAL CONTEXT … diffuse to focal model system

Shaw, P. et al. Arch Gen Psychiatry 2007;64:921-931.

Child ANT

A synaptic model frames our imaging genetic research: LTP in the (mouse) anterior cingulate cortex (Zhuo et al., 2007)

DAGA

BA

GLUTAMATE

+NR2B

-AC1, AC8

-CaMKIV

Jin FanXun Liu

Kevin GuiseLiang Wang

Tobias SommerKarin Brocki

Michael Posner

Thanks toJeff Newcorn