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

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.

SUBMITTER: Macare C

PROVIDER: S-EPMC6525784 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Macare Christine C Ducci Francesca F Zhang Yuning Y Ruggeri Barbara B Jia Tianye T Kaakinen Marika M Kalsi Gursharan G Charoen Pimphen P Casoni Filippo F Peters Jan J Bromberg Uli U Hill Matthew M Buxton Jessica J Blakemore Alexandra A Veijola Juha J Büchel Christian C Banaschewski Tobias T Bokde Arun L W ALW Conrod Patricia P Flor Herta H Frouin Vincent V Gallinat Jürgen J Garavan Hugh H Gowland Penny A PA Heinz Andreas A Ittermann Bernd B Lathrop Mark M Martinot Jean-Luc JL Paus Tomáš T Desrivières Sylvane S Munafò Marcus M Järvelin Marjo-Riitta MR Schumann Gunter G

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 20180811 10

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 × ...[more]

PMID: 30104163

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Project description:ContextThe genetic contribution to liability for opioid dependence is well established; identification of the responsible genes has proved challenging.ObjectiveTo examine association of 1430 candidate gene single-nucleotide polymorphisms (SNPs) with heroin dependence, reporting here only the 71 SNPs in the chromosome 11 gene cluster (NCAM1, TTC12, ANKK1, DRD2) that include the strongest observed associations.DesignCase-control genetic association study that included 2 control groups (lacking an established optimal control group).SettingSemistructured psychiatric interviews.ParticipantsA total of 1459 Australian cases ascertained from opioid replacement therapy clinics, 531 neighborhood controls ascertained from economically disadvantaged areas near opioid replacement therapy clinics, and 1495 unrelated Australian Twin Registry controls not dependent on alcohol or illicit drugs selected from a twin and family sample.Main outcome measureLifetime heroin dependence.ResultsComparison of cases with Australian Twin Registry controls found minimal evidence of association for all chromosome 11 cluster SNPs (P ≥ .01); a similar comparison with neighborhood controls revealed greater differences (P ≥ 1.8 × 10(-4)). Comparing cases (n = 1459) with the subgroup of neighborhood controls not dependent on illicit drugs (n = 340), 3 SNPs were significantly associated (correcting for multiple testing): ANKK1 SNP rs877138 (most strongly associated; odds ratio = 1.59; 95% CI, 1.32-1.92; P = 9.7 × 10(-7)), ANKK1 SNP rs4938013, and TTC12 SNP rs7130431. A similar pattern of association was observed when comparing illicit drug-dependent (n = 191) and nondependent (n = 340) neighborhood controls, suggesting that liability likely extends to nonopioid illicit drug dependence. Aggregate heroin dependence risk associated with 2 SNPs, rs877138 and rs4492854 (located in NCAM1), varied more than 4-fold (P = 2.7 × 10(-9) for the risk-associated linear trend).ConclusionsOur results provide further evidence of association for chromosome 11 gene cluster SNPs with substance dependence, including extension of liability to illicit drug dependence. Our findings highlight the necessity of considering drug exposure history when selecting control groups for genetic investigations of illicit drug dependence.

Dataset Information

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

Publications

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

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