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

The IMAGEN Consortium, Christine Macare, Francesca Ducci, Yuning Zhang, Barbara Ruggeri, Tianye Jia, Marika Kaakinen, Gursharan Kalsi, Pimphen Charoen, Filippo Casoni, Jan Peters, Uli Bromberg, Matthew Hill, Jessica Buxton, Alexandra Blakemore, Juha Veijola, Christian Büchel, Tobias Banaschewski, Arun L.W. Bokde, Patricia ConrodHerta Flor, Vincent Frouin, Jürgen Gallinat, Hugh Garavan, Penny A. Gowland, Andreas Heinz, Bernd Ittermann, Mark Lathrop, Jean-Luc Martinot, Tomáš Paus, Sylvane Desrivières, Marcus Munafò, Marjo-Riitta Järvelin, Gunter Schumann

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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.
Original languageEnglish
Pages (from-to)1103-1114
Number of pages12
JournalEuropean Neuropsychopharmacology
Issue number10
Early online date11 Aug 2018
Publication statusPublished - Oct 2018


  • fMRI
  • Genetics
  • Meta-analysis
  • Risk taking
  • Smoking


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