imaging genetic pathways translational research strategy John A. Fossella www.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”

MAOA NRG1 DRD4 DAT1 etc. “ xeno-phenocopy” validity problem in translational research MAOA NRG1 DRD4 DAT1 etc.

MAOA NRG1 DRD4 DAT1 etc. MAOA NRG1 DRD4 DAT1 etc.

Is the population of planet Earth large enough to minimize type I & type II error ? “ Millions” x “thousands” x “hundreds” (genetic variants) (voxels) (task contrasts)

relevance to many disorders post-natal developmental trajectory well studied anatomically well 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

Human Attention Network Task (ANT) TASK …

Distribution of normalized scores for executive attention N = 200 normal adult volunteers Stimulus-Response conflict score TASK … RELIABILITY is there sufficient or too much variation ? 0 10 20 30 40 50 60 70 80 90 0.05 0.15 0.25 0.35 This group “ Slows down” during incongruent trials

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 ?

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 Orienting Conflict RT _____________________________________________ h 2 F = 2 ( r MZ – r DZ ) .18 -.59 .89 .16 h 2 H = ( r MZ – r DZ )/ .14 -.49 .62 .24 (1 – r DZ ) ML fit: h 2 .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 14 DYS19 14 DYS391 10 DYS439 10 DYS389-1 12 DYS389-2 17 DYS388 12 DYS390 22 DYS426 11 DYS385a 15 DYS385b 16 DYS392 11 HAPLOTYPE “G” Saudi Arabia, Iraq, Iran, Pakistan

INTERPRETATION… internally & externally consistent with literature ? Low DA levels High DA levels 20 30 N = VAR00002 2.00 1.00 Mean +- 1 SE VAR00001 .24 .22 .20 .18 .16 .14 .12 Conflict ratio score COMT Val 108/158 MAOA long prom. repeat COMT Met 108/158 MAOA short prom. repeat

INTERPRETATION … internal & external robustness Fan et al., 2003 MAOA (4-repeat) – (3-repeat) 4-repeat, LOW MA 3-repeat, Hi MA Reaction Time Diff Red = activity biased by MAOA 4-repeat allele Blue = activity biased by MAOA 3-repeat allele

INTERPRETATION … is the inter-subject variation coming from a meaningful source ? 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) DA GABA GLUTAMATE +NR2B -AC1, AC8 -CaMKIV

Jin Fan Xun Liu Kevin Guise Liang Wang Tobias Sommer Karin Brocki Michael Posner Thanks to Jeff Newcorn