title: Functional Genetic Variation in Dopamine Signaling Moderates Prefrontal Cortical Activity During Risky Decision Making.
abstract: Brain imaging has revealed links between prefrontal activity during risky decision-making and striatal dopamine receptors. Specifically, striatal dopamine D2-like receptor availability is correlated with risk-taking behavior and sensitivity of prefrontal activation to risk in the Balloon Analogue Risk Task (BART). The extent to which these associations, involving a single neurochemical measure, reflect more general effects of dopaminergic functioning on risky decision making, however, is unknown. Here, 65 healthy participants provided genotypes and performed the BART during functional magnetic resonance imaging. For each participant, dopamine function was assessed using a gene composite score combining known functional variation across five genes involved in dopaminergic signaling: DRD2, DRD3, DRD4, DAT1, and COMT. The gene composite score was negatively related to dorsolateral prefrontal cortical function during risky decision making, and nonlinearly related to earnings on the task. Iterative permutations of all possible allelic variations (7777 allelic combinations) was tested on brain function in an independently defined region of the prefrontal cortex and confirmed empirical validity of the composite score, which yielded stronger association than 95% of all other possible combinations. The gene composite score also accounted for a greater proportion of variability in neural and behavioral measures than the independent effects of each gene variant, indicating that the combined effects of functional dopamine pathway genes can provide a robust assessment, presumably reflecting the cumulative and potentially interactive effects on brain function. Our findings support the view that the links between dopaminergic signaling, prefrontal function, and decision making vary as a function of dopamine signaling capacity.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences and Semel Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Milky
authors.initials: M
authors.lastname: Kohno
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences and Semel Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Nurmi
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences and Semel Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Laughlin
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences and Semel Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Morales
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences and Semel Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Emma H
authors.initials: EH
authors.lastname: Gail
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences and Semel Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Gerhard S
authors.initials: GS
authors.lastname: Hellemann
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences and Semel Institute, University of California Los Angeles, Los Angeles, CA, USA.|Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.|Brain Research Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Edythe D
authors.initials: ED
authors.lastname: London
mesh_terms: D000293:Adolescent; D000328:Adult; D001931:Brain Mapping; D002394:Catechol O-Methyltransferase / Q000235:genetics; D003657:Decision Making / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050637:Receptors, Dopamine D3 / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics; D012309:Risk-Taking; D055815:Young Adult
chemical_list: C581293:DRD2 protein, human; C493593:DRD3 protein, human; C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C493214:SLC6A3 protein, human; D050638:Receptors, Dopamine D4; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D004298:Dopamine