imaging genetic pathways translational research strategy John A. Fossella www.slideshare.net/johnfossella
May 24, 2015
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