Genetic variation in AKT1 is linked to dopamine-associated prefrontal cortical structure and function in humans.
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 gray-matter 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.
Tan
Hao-Yang
HY
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, NIH, Bethesda, Maryland 20892, USA.
Nicodemus
Kristin K
KK
Chen
Qiang
Q
Li
Zhen
Z
Brooke
Jennifer K
JK
Honea
Robyn
R
Kolachana
Bhaskar S
BS
Straub
Richard E
RE
Meyer-Lindenberg
Andreas
A
Sei
Yoshitasu
Y
Mattay
Venkata S
VS
Callicott
Joseph H
JH
Weinberger
Daniel R
DR
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D003071:Cognition; D004298:Dopamine / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*; D015398:Signal Transduction
D051057:Proto-Oncogene Proteins c-akt; D004298:Dopamine