title: Epistatic interactions of AKT1 on human medial temporal lobe biology and pharmacogenetic implications.
abstract: AKT1 controls important processes in medial temporal lobe (MTL) development and plasticity, but the impact of human genetic variation in AKT1 on these processes is not known in healthy or disease states. Here, we report that an AKT1 variant (rs1130233) previously associated with AKT1 protein expression, prefrontal function and schizophrenia, affects human MTL structure and memory function. Further, supporting AKT1's role in transducing hippocampal neuroplasticity and dopaminergic processes, we found epistasis with functional polymorphisms in BDNF and COMT--genes also implicated in MTL biology related to AKT1. Consistent with prior predictions that these biologic processes relate to schizophrenia, we found epistasis between the same AKT1, BDNF and COMT functional variants on schizophrenia risk, and pharmacogenetic interactions of AKT1 with the effects on cognition and brain volume measures by AKT1 activators in common clinical use--lithium and sodium valproate. Our findings suggest that AKT1 affects risk for schizophrenia and accompanying cognitive deficits, at least in part through specific genetic interactions related to brain neuroplasticity and development, and that these AKT1 effects may be pharmacologically modulated in patients.
authors.affiliation: Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, Bethesda, MD 20892, USA.
authors.forename: H Y
authors.initials: HY
authors.lastname: Tan
authors.forename: A G
authors.initials: AG
authors.lastname: Chen
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.forename: L B
authors.initials: LB
authors.lastname: Browne
authors.forename: B
authors.initials: B
authors.lastname: Verchinski
authors.forename: B
authors.initials: B
authors.lastname: Kolachana
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Apud
authors.forename: J H
authors.initials: JH
authors.lastname: Callicott
authors.forename: V S
authors.initials: VS
authors.lastname: Mattay
authors.forename: D R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D014150:Antipsychotic Agents / Q000627:therapeutic use; D001931:Brain Mapping; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002394:Catechol O-Methyltransferase / Q000235:genetics; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D017850:Economics, Pharmaceutical; D004843:Epistasis, Genetic / Q000187:drug effects / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D010775:Photic Stimulation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D013702:Temporal Lobe / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*
chemical_list: D014150:Antipsychotic Agents; D019208:Brain-Derived Neurotrophic Factor; D002394:Catechol O-Methyltransferase; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen