A neurobiological pathway to smoking in adolescence: TTC12-ANKK1-DRD2 variants and reward response

C Macare, F Ducci, Y Zhang, B Ruggeri, T Jia, M Kaakinen, G Kalsi, P Charoen, F Casoni, J Peters, U Bromberg, M Hill, J Buxton, A Blakemore, J Veijola, C Büchel, T Banaschewski, ALW Bokde, P Conrod, H FlorV Frouin, J Gallinat, H Garavan, PA Gowland, A Heinz, B Ittermann, M Lathrop, JL Martinot, T Paus, S Desrivières, M Munafò, MR Järvelin, G Schumann, The IMAGEN Consortium

Research output: Contribution to journalArticlepeer-review


The TTC12-ANKK1-DRD2 gene-cluster has been implicated in adult smoking. Here, we investigated the contribution of individual genes in the TTC12-ANKK1-DRD2 cluster in smoking and their association with smoking-associated reward processing in adolescence. A meta-analysis of TTC12-ANKK1-DRD2 variants and self-reported smoking behaviours was performed in four European adolescent cohorts (N = 14,084). The minor G-allele of rs2236709, mapping TTC12, was associated with self-reported smoking (p = 5.0 × 10−4) and higher plasma cotinine levels (p = 7.0 × 10−5). This risk allele was linked to an increased ventral-striatal blood-oxygen level-dependent (BOLD) response during reward anticipation (n = 1,263) and with higher DRD2 gene expression in the striatum (p = 0.013), but not with TTC12 or ANKK gene expression. These data suggest a role for the TTC12-ANKK1-DRD2 gene-cluster in adolescent smoking behaviours, provide evidence for the involvement of DRD2 in the early stages of addiction and support the notion that genetically-driven inter-individual differences in dopaminergic transmission mediate reward sensitivity and risk to smoking. © 2018
Original languageEnglish
Pages (from-to)1103-1114
Number of pages12
JournalEuropean Neuropsychopharmacology
Issue number10
Publication statusPublished - 2018


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