Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition.
Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), encoded by PPP1R1B, is a pivotal integrator of information in dopaminoceptive neurons, regulating the response to neuroleptics, psychotomimetics, and drugs of abuse, and affecting striatal function and plasticity. Despite extensive preclinical work, there are almost no data on DARPP-32 function in humans. Here, we identify, through resequencing in 298 chromosomes, a frequent PPP1R1B haplotype predicting mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests that depend on frontostriatal function. Multimodal imaging of healthy subjects revealed an impact of the haplotype on neostriatal volume, activation, and the functional connectivity of the prefrontal cortex. The haplotype was associated with the risk for schizophrenia in 1 family-based association analysis. Our convergent results identify a prefrontal-neostriatal system affected by variation in PPP1R1B and suggest that DARPP-32 plays a pivotal role in cognitive function and possibly in the pathogenesis of schizophrenia.
Meyer-Lindenberg
Andreas
A
Unit for Systems Neuroscience in Psychiatry, Neuroimaging Core Facility, and Clinical Brain Disorders Branch, Genes, Cognition, and Psychosis Program, National Institute for Mental Health (NIMH), NIH, Bethesda, MD 20892, USA.
Straub
Richard E
RE
Lipska
Barbara K
BK
Verchinski
Beth A
BA
Goldberg
Terry
T
Callicott
Joseph H
JH
Egan
Michael F
MF
Huffaker
Stephen S
SS
Mattay
Venkata S
VS
Kolachana
Bhaskar
B
Kleinman
Joel E
JE
Weinberger
Daniel R
DR
D002877:Chromosomes, Human / Q000235:genetics; D003071:Cognition / Q000502:physiology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000502:physiology*; D006239:Haplotypes; D006801:Humans; D017072:Neostriatum / Q000033:anatomy & histology / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000033:anatomy & histology / Q000502:physiology*; D012306:Risk; D012559:Schizophrenia / Q000235:genetics*; D017422:Sequence Analysis, DNA
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497928:PPP1R1B protein, human