Association of a variant in the muscarinic acetylcholine receptor 2 gene (CHRM2) with nicotine addiction

Abstract

Genetic factors contribute to the overall risk of developing nicotine addiction, which is the major cause of preventable deaths in western countries. However, knowledge regarding specific polymorphisms influencing smoking phenotypes remains scarce. In the present study we provide evidence that a common single nucleotide polymorphism (SNP) in the 5' untranslated region of CHRM2, the gene coding for the muscarinic acetylcholine receptor 2 is associated with nicotine addiction. CHRM2 was defined as a candidate gene for nicotine addiction based on previous evidence that linked variations in CHRM2 to alcohol and drug dependence. A total of more than 5,500 subjects representative of the German population were genotyped and assessed regarding their smoking habits. The impact of three SNPs in CHRM2 on smoking behavior/nicotine addiction was investigated using logistic regression models or a quasi-Poisson regression model, respectively. We found the T allele of SNP rs324650 to be associated with an increased risk of smoking/nicotine dependence according to three different models, the recessive models of regular or heavy smokers vs. never-smokers (odds ratio 1.17 in both analyses) and according to the Fagerström index of nicotine addiction. In the analysis stratified by gender this association was only found in females. Our data provide further evidence that variations in CHRM2 may be associated with the genetic risk of addiction in general or with certain personality traits that predispose to the development of addiction. Alternatively, variations in CHRM2 could modulate presynaptic auto-regulation in cholinergic systems and may thereby affect an individual's response to nicotine more specifically.

Muscarinic Receptors: Their Roles in Disorders of the Central Nervous System and Potential as Therapeutic Targets

“…Variations in the M2 gene sequence were associated with a combination of alcohol and comorbid drug dependence, but not alcohol dependence alone [89]. More recently, variations in the M2 receptor gene sequence have been associated with an increased risk of smoking/nicotine dependence [90]. Together these data suggest that the muscarinic system may have a role in the pathophysiology of addiction, however, the exact nature of this role requires further elucidation.…”

Electronic cigarettes and thirdhand tobacco smoke: two emerging health care challenges for the primary care provider

“…Once thought to be a “habit” or “custom”, cigarette smoking and other forms of tobacco use are now widely recognized as behaviors driven by nicotine addiction. It is addiction to nicotine that compels many smokers to continue to use tobacco products even when they appreciate its harmful effects and wish to quit 3,4…”

A Genome-Wide Association Study of Behavioral Disinhibition

“…Other studies have reported significant associations between GABRA2 and indicators of polysubstance abuse (Corley et al, 2008; Drgon, D’Addario, & Uhl, 2006) and antisocial behavior (Corley et al, 2008; Dick et al, 2006; Dick et al, 2009). Similarly, variation in the gene coding for the cholinergic muscarinic receptor 2 (CHRM2) has been associated with risk for smoking (Mobascher et al, 2010), comorbid alcohol dependence and drug dependence (Dick et al, 2007), and multiple indicators of externalizing psychopathology, including symptom counts for alcohol dependence, illicit drug dependence, childhood conduct disorder, and adult antisocial personality disorder as well as personality indicators of novelty seeking and sensation seeking (Dick et al, 2008). …”