title: Genetic risk for nicotine dependence in the cholinergic system and activation of the brain reward system in healthy adolescents.
abstract: Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents, we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex (ACC), and personality traits related to addiction. In both samples, carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal ACC but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared with AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the ACC to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus, it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes.
authors.affiliation: Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Nees
authors.forename: S H
authors.initials: SH
authors.lastname: Witt
authors.forename: A
authors.initials: A
authors.lastname: Lourdusamy
authors.forename: S
authors.initials: S
authors.lastname: Vollstädt-Klein
authors.forename: S
authors.initials: S
authors.lastname: Steiner
authors.forename: L
authors.initials: L
authors.lastname: Poustka
authors.forename: T
authors.initials: T
authors.lastname: Banaschewski
authors.forename: G J
authors.initials: GJ
authors.lastname: Barker
authors.forename: C
authors.initials: C
authors.lastname: Büchel
authors.forename: P J
authors.initials: PJ
authors.lastname: Conrod
authors.forename: J
authors.initials: J
authors.lastname: Frank
authors.forename: J
authors.initials: J
authors.lastname: Gallinat
authors.forename: H
authors.initials: H
authors.lastname: Garavan
authors.forename: A
authors.initials: A
authors.lastname: Heinz
authors.forename: B
authors.initials: B
authors.lastname: Ittermann
authors.forename: E
authors.initials: E
authors.lastname: Loth
authors.forename: K
authors.initials: K
authors.lastname: Mann
authors.forename: E
authors.initials: E
authors.lastname: Artiges
authors.forename: T
authors.initials: T
authors.lastname: Paus
authors.forename: Z
authors.initials: Z
authors.lastname: Pausova
authors.forename: M N
authors.initials: MN
authors.lastname: Smolka
authors.forename: M
authors.initials: M
authors.lastname: Struve
authors.forename: G
authors.initials: G
authors.lastname: Schumann
authors.forename: M
authors.initials: M
authors.lastname: Rietschel
authors.forename: H
authors.initials: H
authors.lastname: Flor
mesh_terms: D000293:Adolescent; D000294:Adolescent Behavior / Q000523:psychology*; D003342:Corpus Striatum / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000502:physiology; D059907:Functional Neuroimaging; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006179:Gyrus Cinguli / Q000502:physiology; D006262:Health; D006801:Humans; D008297:Male; D005810:Multigene Family / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010551:Personality / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012201:Reward; D012307:Risk Factors; D014029:Tobacco Use Disorder / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D044465:White People / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human