TY - JOUR
T1 - Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans
AU - Tan, Hao Yang
AU - Nicodemus, Kristin K.
AU - Chen, Qiang
AU - Li, Zhen
AU - Brooke, Jennifer K.
AU - Honea, Robyn
AU - Kolachana, Bhaskar S.
AU - Straub, Richard E.
AU - Meyer-Lindenberg, Andreas
AU - Sei, Yoshitasu
AU - Mattay, Venkata S.
AU - Callicott, Joseph H.
AU - Weinberger, Daniel R.
PY - 2008/6/2
Y1 - 2008/6/2
N2 - AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal graymatter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis.
AB - AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. Here, we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts influenced several brain measures related to dopaminergic function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal graymatter volume on MRI were altered in subjects with the AKT1 variation. Moreover, on neuroimaging measures with a main effect of the AKT1 genotype, there was significant epistasis with a functional polymorphism (Val158Met) in catechol-O-methyltransferase [COMT], a gene that indexes cortical synaptic dopamine. This genetic interaction was consistent with the putative role of AKT1 in dopaminergic signaling. Supportive of an earlier tentative association of AKT1 with schizophrenia, we also found that this AKT1 variant was associated with risk for schizophrenia. These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggest that the mechanism of this effect may be coupled to dopaminergic signaling and relevant to the expression of psychosis.
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U2 - 10.1172/JCI34725
DO - 10.1172/JCI34725
M3 - Article
C2 - 18497887
AN - SCOPUS:45749149476
SN - 0021-9738
VL - 118
SP - 2200
EP - 2208
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -