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

paper Cited Public

Authors: Ducci, Francesca; Kaakinen, Marika; Pouta, Anneli; Hartikainen, Anna-Liisa; Veijola, Juha; Isohanni, Matti; Charoen, Pimphen; Coin, Lachlan; Hoggart, Clive; Ekelund, Jesper; Peltonen, Leena; Freimer, Nelson; Elliott, Paul; Schumann, Gunter; Järvelin, Marjo-Riitta
Year: 2011
Journal: Biological psychiatry
PMID: 21168125
DOI: 10.1016/j.biopsych.2010.09.055
PMCID: PMC3058144

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.

#	Section	Preview
0	INTRODUCTION	Tobacco smoking is the largest avoidable cause of morbidity and mortality in developed countries.…
1	INTRODUCTION	Although a large number of genetic loci potentially moderating smoking have been tested, only a few…
2	INTRODUCTION	The CHRNA5-CHRNA3-CHRNB4 gene-cluster encodes for the nicotinic acetylcholine receptor subunits…
3	INTRODUCTION	The dopamine receptor 2 (DRD2), the ankyrin repeat and kinase domain containing 1 (ANKK1), and…
4	INTRODUCTION	Up to date, most of the genetic studies on smoking have focused on adulthood and little is known…
5	INTRODUCTION	and combined effects of common polymorphisms within CHRNA5-CHRNA3-CHRNB4 and TTC12-ANKK1-DRD2…
6	METHODS — Participants	We studied a subset of 4,762 individuals with phenotypic/genotypic data available from the general…
7	METHODS — Smoking-related variables	At age 14, participants reported via a postal questionnaire if they smoked and how much using eight…
8	METHODS — Smoking-related variables	At age 31 participants reported via postal questionnaire if they had ever smoked, and the number of…
9	METHODS — Smoking-related variables	Although smoking at 14 and 31 years were collected using different questions, there was a stepwise…
10	METHODS — Smoking-related variables	Participants were classified based on change/persistence of their smoking habits from 14 to 31 years…
11	METHODS — Smoking-related variables	Participants’ mothers’ smoking habits were assessed during pregnancy(39). Mothers were…
12	METHODS — Novelty seeking	Novelty seeking was assessed at age 31 using the Temperament and Character Inventory…
13	METHODS — Socio-demographic factors	Family socio-economic status, based on father’s occupation, was collected during pregnancy and at…
14	METHODS — Socio-demographic factors	Cohort members’ socio-economic status based on occupation was collected at 31 years and classified…
15	METHODS — Socio-demographic factors	Mothers’ marital status during pregnancy was dichotomised into married versus unmarried (singles,…
16	METHODS — Genotyping	Genome-wide genotyping was performed at the Broad Institute Biological Sample Repository in ~5,000…
17	METHODS — Genotyping	Distributions of the different variables in the study sample and in participants who were excluded…
18	METHODS — Statistical analyses	Primary association analyses were performed between all SNPs in the two chromosome regions and…
19	METHODS — Statistical analyses	The most statistically significant SNPs, namely CHRNA3-rs1051730 and TTC12-rs10502172, were selected…

Name	Type
15q25 locus	variant
AAGGGAAAAGGGACGGGA local	variant
adolescents	cohort
adulthood	cohort
age 31 local	cohort
alcohol dependence	phenotype
ANKK1	gene
Broad Institute Biological Sample Repository local	cohort
Chrna3	gene
CHRNA3 rs1051730 local	variant
CHRNA3 rs1051730 A local	variant
CHRNA5	gene
CHRNA5-CHRNA3-CHRNB4 cluster	gene
Chrnb4	gene
cigarettes	phenotype
cohort members	cohort
Community-ascertained sample local	cohort
current-smokers local	phenotype
decreased response to nicotine agonists in vitro local	phenotype
DRD2	gene
eagerness to participate local	phenotype
early initiation	phenotype
ever smoking	phenotype
Family socio-economic status local	phenotype
farmers local	phenotype
GGGGAGGGAGAGGAGGGG local	variant
haplotype-block 1 local	variant
haplotype-block 2 local	variant
heavy drinking	phenotype
heavy maternal smoking local	phenotype
heavy/regular-smoker local	phenotype
heavy/regular smoking local	phenotype
heavy-smoker local	phenotype
heavy-smokers local	phenotype
Heavy-smokers local	phenotype
Heavy-smokers at age 31 local	phenotype
heavy smoking	phenotype
heavy-smoking local	phenotype
Heavy smoking at age 31 local	phenotype
heavy use in mid-adulthood local	phenotype
high novelty seeking local	phenotype
High novelty seeking local	phenotype
high-quantity smokers local	phenotype
Illumina Infinium 370cnvDuo array local	drug
inability to quit smoking in pregnancy local	phenotype
late onset-smoker local	phenotype
light maternal smoking local	phenotype
light/non-smoker local	phenotype
Light+non-smokers local	phenotype
light/occasional smoking local	phenotype
light-smoker local	phenotype
light-smokers local	phenotype
Light-smokers local	phenotype
light-smoking local	phenotype
low-quantity smoker local	phenotype
low-quantity smokers local	phenotype
Low socio-economic status local	phenotype
lung cancer	phenotype
marital status	phenotype
maternal smoking	phenotype
Maternal smoking before pregnancy local	drug
men	cohort
mid-adulthood local	cohort
Mothers of participants local	cohort
never smokers	phenotype
nicotine	drug
nicotine addiction	phenotype
nicotine agonists local	drug
nicotine dependence	phenotype
nicotine response local	phenotype
nicotine use	phenotype
non-participants local	cohort
non-smokers	phenotype
Northern Finland 1966 Birth Cohort local	cohort
novelty seeking	phenotype
number of cigarettes smoked per day	phenotype
Occasional smoker local	phenotype
occasional smokers	phenotype
Occasional-smokers at age 14 local	phenotype
occasional smoking at 14 local	phenotype
offspring	cohort
offspring of heavy smoking mothers local	cohort
offspring of light smoking mothers local	cohort
offspring of non-smoking mothers local	cohort
Offspring smoking	phenotype
opioid dependence	phenotype
Other drug dependencies local	phenotype
Parental attitudes local	phenotype
participants	cohort
past smokers local	phenotype
Peer influences	phenotype
persistent-smoker local	phenotype
pleasurable response to smoking	phenotype
professionals local	phenotype
Psychosocial factors	phenotype
Regular-smokers at age 14 local	phenotype
regular smoking	phenotype
Regular smoking at age 14 local	phenotype
rs10502172	variant
rs1051730	variant
rs1076563 local	variant
rs16969968	variant
rs2303380 local	variant
rs2734849 local	variant
sex	phenotype
sex hormones	drug
skilled-workers local	phenotype
smoking	phenotype
smoking at 14 local	phenotype
Smoking at 14 years local	phenotype
smoking at 31 local	phenotype
Smoking at 31 years local	phenotype
smoking at age 14 local	phenotype
Smoking at age 14 local	phenotype
smoking behavior	phenotype
smoking behaviour	phenotype
smoking behaviours local	phenotype
smoking in adolescence local	phenotype
smoking in adulthood local	phenotype
smoking initiation	phenotype
smoking occasionally local	phenotype
smoking persistence	phenotype
smoking quantity	phenotype
smoking regularly local	phenotype
smoking severity	phenotype
SNP	cohort
social disadvantage	phenotype
socio-economic status	phenotype
Taq1A (rs1800497) local	variant
tobacco-related diseases local	phenotype
tobacco use	phenotype
TTC12	gene
TTC12-ANKK1-DRD2 local	gene
TTC12 rs10502172 local	variant
TTC12 rs10502172 G local	variant
Unmarried	phenotype
unmarried mothers local	phenotype
Unmarried status during pregnancy local	phenotype
unskilled-worker families local	phenotype
unskilled-workers local	phenotype
vascular disease	phenotype
women	cohort
young cohorts local	cohort

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In this knowledge base

Title	Year	PMID
Converging findings from linkage and association analyses on susceptibility genes for smoking and other addictions.	2016	27166759
Narrative review of genes, environment, and cigarettes.	2016	27124093
Genetic and environmental contributions to the relationships between brain structure and average lifetime cigarette use.	2015	25690561
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ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure.	2013	23303482
Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking.	2013	24186853
Polygenic risk and the developmental progression to heavy, persistent smoking and nicotine dependence: evidence from a 4-decade longitudinal study.	2013	23536134
The genetic basis of addictive disorders.	2012	22640768
Variants located upstream of CHRNB4 on chromosome 15q25.1 are associated with age at onset of daily smoking and habitual smoking.	2012	22438940
Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence.	2011	21683344

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ANAPC1 and SLCO3A1 are associated with nicotine dependence: meta-analysis of genome-wide association studies.	Wang KS et al.	—	2012	→
Associations between variation in CHRNA5-CHRNA3-CHRNB4, body mass index and blood pressure in the Northern Finland Birth Cohort 1966.	Kaakinen M et al.	—	2012	→
Connecting ncRNA Cigarette Smoking Studies with Tobacco Use Behaviors and Health Outcomes.	Ehringer MA	—	2012	→
From men to mice: CHRNA5/CHRNA3, smoking behavior and disease.	Ware JJ et al.	—	2012	→
Genetic factors control nicotine self-administration in isogenic adolescent rat strains.	Chen H et al.	—	2012	→
Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight.	Tyrrell J et al.	—	2012	→
Glutamate and synaptic plasticity systems and smoking behavior: results from a genetic association study.	dos Santos VA et al.	—	2012	→
Risk factors for adolescent smoking: parental smoking and the mediating role of nicotine dependence.	Selya AS et al.	—	2012	→
The genetic basis of addictive disorders.	Ducci F et al.	—	2012	→
Variants located upstream of CHRNB4 on chromosome 15q25.1 are associated with age at onset of daily smoking and habitual smoking.	Kapoor M et al.	—	2012	→
Developmental perspective on the role of genes in smoking risk.	Gelernter J	—	2011	→
Rare nonsynonymous variants in alpha-4 nicotinic acetylcholine receptor gene protect against nicotine dependence.	Xie P et al.	—	2011	→