Dataset Information

Genetics of addictive behavior: the example of nicotine dependence.

ABSTRACT: The majority of addictive disorders have a significant heritability-roughly around 50%. Surprisingly, the most convincing association (a nicotinic acetylcholine receptor CHRNA5-A3-B4 gene cluster in nicotine dependence), with a unique attributable risk of 14%, was detected through a genome-wide association study (GWAS) on lung cancer, although lung cancer has a low heritability. We propose some explanations of this finding, potentially helping to understand how a GWAS strategy can be successful. Many endophenotypes were also assessed as potentially modulating the effect of nicotine, indirectly facilitating the development of nicotine dependence. Challenging the involved phenotype led to the demonstration that other potentially overlapping disorders, such as schizophrenia and Parkinson disease, could also be involved, and further modulated by parent monitoring or the existence of a smoking partner. Such a complex mechanism of action is compatible with a gene-environment interaction, most clearly explained by epigenetic factors, especially as such factors were shown to be, at least partly, genetically driven.

SUBMITTER: Gorwood P

PROVIDER: S-EPMC5741107 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Genetics of addictive behavior: the example of nicotine dependence.

Gorwood Philip P Le Strat Yann Y Ramoz Nicolas N

Dialogues in clinical neuroscience 20170901 3

The majority of addictive disorders have a significant heritability-roughly around 50%. Surprisingly, the most convincing association (a nicotinic acetylcholine receptor <i>CHRNA5-A3-B4</i> gene cluster in nicotine dependence), with a unique attributable risk of 14%, was detected through a genome-wide association study (GWAS) on lung cancer, although lung cancer has a low heritability. We propose some explanations of this finding, potentially helping to understand how a GWAS strategy can be succ ...[more]

PMID: 29302221

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Project description:INTRODUCTION:Identification of modifiable risk factors for suicidal behaviors is a priority for the U.S. Army. This study investigated associations of nicotine dependence with suicidal behaviors among incoming soldiers. METHODS:Lifetime DSM-IV nicotine dependence, mental disorders, suicidal behaviors, and their ages of onset were retrospectively assessed in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) New Soldier Study. Discrete-time survival analysis of person-year data from 30,436 soldiers was performed to evaluate associations of nicotine dependence with subsequent suicidal ideation, plans, and attempts. Among respondents with lifetime ideation (n=4,060), models tested associations of nicotine dependence with progression from ideation to first onset of plan, from plan to first attempt, and, among ideators without plans, from ideation to first unplanned attempt. A hierarchy of models incorporated increasing controls for other risk factors. Data were collected in 2011-2012 and analyzed in 2017-2018. RESULTS:In models controlling for sociodemographic characteristics, nicotine dependence was associated with onset of all suicidal behaviors (AORs, 2.07-4.08, p<0.001) and with each type of progression of suicidal behavior (AORs, 1.48-2.44, p<0.005). After adjusting for childhood adversities and mental disorders, nicotine dependence remained associated with onset of ideation (AOR=1.27, 95% CI=1.10, 1.46, p=0.001) and attempt (AOR=1.83, 95% CI=1.41, 2.37, p<0.001); and with progression from ideation to unplanned attempt (AOR=2.03, 95% CI=1.17, 1.74, p<0.001). CONCLUSIONS:Nicotine dependence exhibited associations with onset of suicidal ideation and suicide attempt-and with progression from ideation to unplanned attempt-that were independent of other measured risk factors. Awareness of associations of nicotine dependence with suicidal behaviors may inform risk assessment, facilitate targeting of prevention efforts, and provide further impetus for reducing nicotine dependence.

Project description:BackgroundClassical genetic studies indicate that nicotine dependence is a substantially heritable complex disorder. Genetic vulnerabilities to nicotine dependence largely overlap with genetic vulnerabilities to dependence on other addictive substances. Successful abstinence from nicotine displays substantial heritable components as well. Some of the heritability for the ability to quit smoking appears to overlap with the genetics of nicotine dependence and some does not. We now report genome wide association studies of nicotine dependent individuals who were successful in abstaining from cigarette smoking, nicotine dependent individuals who were not successful in abstaining and ethnically-matched control subjects free from substantial lifetime use of any addictive substance.ResultsThese data, and their comparison with data that we have previously obtained from comparisons of four other substance dependent vs control samples support two main ideas: 1) Single nucleotide polymorphisms (SNPs) whose allele frequencies distinguish nicotine-dependent from control individuals identify a set of genes that overlaps significantly with the set of genes that contain markers whose allelic frequencies distinguish the four other substance dependent vs control groups (p < 0.018). 2) SNPs whose allelic frequencies distinguish successful vs unsuccessful abstainers cluster in small genomic regions in ways that are highly unlikely to be due to chance (Monte Carlo p < 0.00001).ConclusionThese clustered SNPs nominate candidate genes for successful abstinence from smoking that are implicated in interesting functions: cell adhesion, enzymes, transcriptional regulators, neurotransmitters and receptors and regulation of DNA, RNA and proteins. As these observations are replicated, they will provide an increasingly-strong basis for understanding mechanisms of successful abstinence, for identifying individuals more or less likely to succeed in smoking cessation efforts and for tailoring therapies so that genotypes can help match smokers with the treatments that are most likely to benefit them.

Dataset Information

Genetics of addictive behavior: the example of nicotine dependence.

Publications

Genetics of addictive behavior: the example of nicotine dependence.

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