TY - JOUR
T1 - Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition
AU - Meyer-Lindenberg, Andreas
AU - Straub, Richard E.
AU - Lipska, Barbara K.
AU - Verchinski, Beth A.
AU - Goldberg, Terry
AU - Callicott, Joseph H.
AU - Egan, Michael F.
AU - Huffaker, Stephen S.
AU - Mattay, Venkata S.
AU - Kolachana, Bhaskar
AU - Kleinman, Joel E.
AU - Weinberger, Daniel R.
PY - 2007/3/1
Y1 - 2007/3/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI30413
DO - 10.1172/JCI30413
M3 - Article
C2 - 17290303
AN - SCOPUS:33847407101
SN - 0021-9738
VL - 117
SP - 672
EP - 682
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 3
ER -