TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4 influence different pathways leading to smoking behavior from adolescence to mid-adulthood

Francesca Ducci, Marika Kaakinen, Anneli Pouta, Anna-Liisa Hartikainen, Juha Veijola, Matti Isohanni, Pimphen Charoen, Lachlan Coin, Clive Hoggart, Jesper Ekelund, Leena Peltonen, Nelson Freimer, Paul Elliott, Gunter Schumann, Marjo-Riitta Järvelin, Francesca Ducci, Marika Kaakinen, Anneli Pouta, Anna-Liisa Hartikainen, Juha Veijola, Matti Isohanni, Pimphen Charoen, Lachlan Coin, Clive Hoggart, Jesper Ekelund, Leena Peltonen, Nelson Freimer, Paul Elliott, Gunter Schumann, Marjo-Riitta Järvelin

Abstract

Background: CHRNA5-CHRNA3-CHRNB4 and TTC12-ANKK1-DRD2 gene-clusters influence smoking behavior. Our aim was to test developmental changes in their effects as well as the interplays between them and with nongenetic factors.

Methods: Participants included 4762 subjects from a general population-based, prospective Northern Finland 1966 Birth Cohort (NFBC 1966). Smoking behavior was collected at age 14 and 31 years. Information on maternal smoking, socioeconomic status, and novelty seeking were also collected. Structural equation modeling was used to construct an integrative etiologic model including genetic and nongenetic factors.

Results: Several single nucleotide polymorphisms in both gene-clusters were significantly associated with smoking. The most significant were in CHRNA3 (rs1051730, p = 1.1 × 10(-5)) and in TTC12 (rs10502172, p = 9.1 × 10(-6)). CHRNA3-rs1051730[A] was more common among heavy/regular smokers than nonsmokers with similar effect-sizes at age 14 years (odds ratio [95% CI]: 1.27 [1.06-1.52]) and 31 years (1.28 [1.13-1.44]). TTC12-rs10502172[G] was more common among smokers than nonsmokers with stronger association at 14 years (1.33 [1.11-1.60]) than 31 years (1.14 [1.02-1.28]). In adolescence, carriers of three-four risk alleles at either CHRNA3-rs1051730 or TTC12-rs10502172 had almost threefold odds of smoking regularly than subjects with no risk alleles. TTC12-rs10502172 effect on smoking in adulthood was mediated by its effect on smoking in adolescence and via novelty seeking. Effect of CHRNA3-rs1051730 on smoking in adulthood was direct.

Conclusions: TTC12-ANKK1-DRD2s seemed to influence smoking behavior mainly in adolescence, and its effect is partially mediated by personality characteristics promoting drug-seeking behavior. In contrast, CHRNA5-CHRNA3-CHRNB4 is involved in the transition toward heavy smoking in mid-adulthood and in smoking persistence. Factors related to familial and social disadvantages were strong independent predictors of smoking.

Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Association between smoking behavior during adolescence and adulthood and genetic variation in the two candidate chromosome regions. A and B: the 11q23 region; C and D: the 15q25 region. Blue diamond indicates the most significantly associated SNP. For other SNPs, diamonds are colored in a white-to-red scale corresponding to r2 values from 0 to 1 with either rs1051730 or rs10502172. SNP position refers to NCBI build 35. Estimated recombination rates are from Hapmap and gene annotations from UCSC genome browser using build 35 coordinates.
Figure 2
Figure 2
Combined effect of CHRNA3-rs1051730 and TTC12-rs10502172 on smoking behavior in adolescence and mid-adulthood. Odds ratios (OR) and 95% confidence intervals (CI) are computed using multinomial logistic regression and adjusted for principal components, gender, maternal smoking during pregnancy, and socio-economic status.
Figure 3
Figure 3
Integrative etiological model for smoking behavior from adolescence to mid-adulthood. Path coefficients are standardized probit regression estimates computed via structural equation modeling, and thicknesses of path lines are proportional to the estimates. Non-significant (p>0.05) paths are shown with dashed lines. Socio-economic status at 31: Others: students, pensioners, long-term unemployed, not defined. Maternal smoking: smokers are compared to non-smokers; smoking at 14 years: smokers are compared to non-smokers; smoking at 31 years: heavy-smokers are compared to light/non-smokers.

Source: PubMed

3
Sottoscrivi