title: From gene to brain to behavior: schizophrenia-associated variation in AMBRA1 alters impulsivity-related traits.
abstract: Recently, genome-wide association between schizophrenia and an intronic variant in AMBRA1 (rs11819869) was reported. Additionally, in a reverse genetic approach in adult healthy subjects, risk allele carriers showed a higher medial prefrontal cortex blood oxygen level-dependent (BOLD) response during a flanker task examining motor inhibition as an aspect of impulsivity. To test whether this finding can be expanded to further aspects of impulsivity, we analysed the effects of the rs11819869 genotype on impulsivity-related traits on a behavioral, temperament and neural level in a large sample of healthy adolescents. We consider this reverse genetic approach specifically suited for use in a healthy adolescent sample, as these individuals comprise those who will eventually develop mental disorders in which impulsivity is implicated. Healthy adolescents from the IMAGEN study were included in the neuropsychological analysis (n = 848) and a functional magnetic resonance imaging (fMRI) task (n = 512). Various aspects of impulsivity were assessed using the Temperament and Character Inventory-Revised, the Substance Use Risk Profile Scale, the Cambridge Cognition Neuropsychological Test Automated Battery, and the Stop Signal Task (SST) in the fMRI paradigm. On a behavioral level, increased delay aversion was observed in risk allele carriers. Furthermore, risk allele carriers showed a higher BOLD response in an orbito-frontal target region during the SST, which declined to trend status after Family Wise Error correction. Our findings support the hypothesis that the schizophrenia-related risk variant of rs11819869 is involved in various aspects of impulsivity, and that this involvement occurs on a behavioral as well as an imaging genetics level.
authors.affiliation: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Square J5, Mannheim, 68159, Germany; Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Heinrich
authors.forename: Frauke
authors.initials: F
authors.lastname: Nees
authors.forename: Anbarasu
authors.initials: A
authors.lastname: Lourdusamy
authors.forename: Jelka
authors.initials: J
authors.lastname: Tzschoppe
authors.forename: Sandra
authors.initials: S
authors.lastname: Meier
authors.forename: Sabine
authors.initials: S
authors.lastname: Vollstädt-Klein
authors.forename: Mira
authors.initials: M
authors.lastname: Fauth-Bühler
authors.forename: Sabina
authors.initials: S
authors.lastname: Steiner
authors.forename: Christiane
authors.initials: C
authors.lastname: Bach
authors.forename: Luise
authors.initials: L
authors.lastname: Poustka
authors.forename: Tobias
authors.initials: T
authors.lastname: Banaschewski
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Barker
authors.forename: Christian
authors.initials: C
authors.lastname: Büchel
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Conrod
authors.forename: Hugh
authors.initials: H
authors.lastname: Garavan
authors.forename: Jürgen
authors.initials: J
authors.lastname: Gallinat
authors.forename: Andreas
authors.initials: A
authors.lastname: Heinz
authors.forename: Bernd
authors.initials: B
authors.lastname: Ittermann
authors.forename: Eva
authors.initials: E
authors.lastname: Loth
authors.forename: Karl
authors.initials: K
authors.lastname: Mann
authors.forename: Eric
authors.initials: E
authors.lastname: Artiges
authors.forename: Tomáš
authors.initials: T
authors.lastname: Paus
authors.forename: Claire
authors.initials: C
authors.lastname: Lawrence
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Pausova
authors.forename: Michael N
authors.initials: MN
authors.lastname: Smolka
authors.forename: Andreas
authors.initials: A
authors.lastname: Ströhle
authors.forename: Maren
authors.initials: M
authors.lastname: Struve
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Witt
authors.forename: Gunter
authors.initials: G
authors.lastname: Schumann
authors.forename: Herta
authors.initials: H
authors.lastname: Flor
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D001921:Brain / Q000502:physiology*; D005260:Female; D006801:Humans; D007175:Impulsive Behavior / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics
chemical_list: C553334:AMBRA1 protein, human; D048868:Adaptor Proteins, Signal Transducing
keywords: adolescents; behavior; genotype; imaging genetics