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

Eur Neuropsychopharmacol. 2018 Oct;28(10):1103-1114. doi: 10.1016/j.euroneuro.2018.07.101. Epub 2018 Aug 11.

Abstract

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.

Keywords: Genetics; IMAGEN-ALSPAC-NFBC; Meta-analysis; Risk taking; Smoking; fMRI.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adolescent Behavior / physiology
  • Adolescent Behavior / psychology
  • Anticipation, Psychological / physiology
  • Behavior, Addictive / diagnostic imaging
  • Behavior, Addictive / genetics
  • Behavior, Addictive / physiopathology
  • Behavior, Addictive / psychology
  • Brain / diagnostic imaging
  • Brain / physiopathology
  • Cotinine / blood
  • Female
  • Genetic Association Studies
  • Genetic Variation
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Protein-Serine-Threonine Kinases / genetics*
  • Proteins / genetics*
  • Receptors, Dopamine D2 / genetics*
  • Reward*
  • Smoking / genetics*
  • Smoking / physiopathology
  • Smoking / psychology*

Substances

  • DRD2 protein, human
  • Proteins
  • Receptors, Dopamine D2
  • TTC12 protein, human
  • ANKK1 protein, human
  • Protein-Serine-Threonine Kinases
  • Cotinine