title: Effect of GABRA2 genotype on development of incentive-motivation circuitry in a sample enriched for alcoholism risk.
abstract: Heightened reactivity of the incentive-motivation system has been proposed to underlie adolescent-typical risky behaviors, including problem alcohol involvement. However, even in adolescence considerable individual variation in these behaviors exists, which may have genetic underpinnings and be related to variations in risk for later alcohol use disorder (AUD). Variants in GABRA2 have been associated with adult alcohol dependence as well as phenotypic precursors, including impulsiveness and externalizing behaviors. We investigated the impact of GABRA2 on the developmental trajectory of nucleus accumbens (NAcc) activation during anticipation of monetary reward from childhood to young adulthood. Functional MRI during a monetary incentive delay task was collected in 175 participants, with the majority (n = 151) undergoing repeated scanning at 1- to 2-year intervals. One group entered the study at age 8-13 years (n = 76) and another entered at age 18-23 years (n = 99). Most participants were children of alcoholics (79%) and thus at heightened risk for AUD. A total of 473 sessions were completed, covering ages 8-27 years. NAcc activation was heightened during adolescence compared with childhood and young adulthood. GABRA2 genotype (SNP rs279858) was associated with individual differences in NAcc activation specifically during adolescence, with the minor allele (G) associated with greater activation. Furthermore, NAcc activation mediated an effect of genotype on alcohol problems (n = 104). This work demonstrates an impact of GABRA2 genotype on incentive-motivation neurocircuitry in adolescence, with implications for vulnerability to alcoholism. These findings represent an important step toward understanding the genetic and neural basis of individual differences in how risk for addiction unfolds across development.
authors: 1] Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA [2] Addiction Research Center, University of Michigan, Ann Arbor, MI, USA.
authors: Mary M
authors: MM
authors: Heitzeg
authors: 1] Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA [2] Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors: Sandra
authors: S
authors: Villafuerte
authors: 1] Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA [2] Addiction Research Center, University of Michigan, Ann Arbor, MI, USA [3] Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
authors: Barbara J
authors: BJ
authors: Weiland
authors: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
authors: Mary-Anne
authors: MA
authors: Enoch
authors: 1] Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA [2] Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA [3] Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
authors: Margit
authors: M
authors: Burmeister
authors: 1] Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA [2] Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.
authors: Jon-Kar
authors: JK
authors: Zubieta
authors: 1] Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA [2] Addiction Research Center, University of Michigan, Ann Arbor, MI, USA.
authors: Robert A
authors: RA
authors: Zucker
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000437:Alcoholism / Q000150:complications / Q000235:genetics; D000704:Analysis of Variance; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002648:Child; D002658:Developmental Disabilities / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D009042:Motivation / Q000235:genetics*; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011963:Receptors, GABA-A / Q000235:genetics*; D055815:Young Adult
chemical_list: C484841:GABRA2 protein, human; D011963:Receptors, GABA-A; D010100:Oxygen