Crucial roles of the CHRNB3–CHRNA6 gene cluster on chromosome 8 in nicotine dependence: update and subjects for future research

Abstract

Cigarette smoking is a leading cause of preventable death throughout the world. Nicotine, the primary addictive compound in tobacco, plays a vital role in the initiation and maintenance of its use. Nicotine exerts its pharmacological roles through nicotinic acetylcholine receptors (nAChRs), which are ligand-gated ion channels consisting of five membrane-spanning subunits. Besides the CHRNA4, CHRNB2 and CHRNA5/A3/B4 cluster on chromosome 15, which has been investigated intensively, recent evidence from both genome-wide association studies and candidate gene-based association studies has revealed the crucial roles of the CHRNB3–CHRNA6 gene cluster on chromosome 8 in nicotine dependence (ND). These studies demonstrate two distinct loci within this region. The first one is tagged by rs13277254, upstream of the CHRNB3 gene, and the other is tagged by rs4952, a coding single nucleotide polymorphism in exon 5 of that gene. Functional studies by genetic manipulation in mice have shown that α6*-nAChRs, located in the ventral tegmental area (VTA), are of great importance in controlling nicotine self-administration. However, when the α6 subunit is selectively re-expressed in the VTA of the α6−/− mouse by a lentiviral vector, the reinforcing property of nicotine is restored. To further determine the role of α6*-nAChRs in the process of nicotine-induced reward and withdrawal, genetic knock-in strains have been examined, which showed that replacement of Leu with Ser in the 9′ residue in the M2 domain of α6 produces nicotine-hypersensitive mice (α6 L9′S) with enhanced dopamine release. Moreover, nicotine-induced upregulation may be another ingredient in the pathology of nicotine addiction although the effect of chronic nicotine exposure on the expression of α6-containing receptors is controversial. To gain a better understanding of the pathological processes underlying ND and ND-related behaviors and to promote the development of effective smoking cessation therapies, we here present the most recent studies concerning the genetic effects of the CHRNB3–CHRNA6 gene cluster in ND.

Alpha6-Containing Nicotinic Acetylcholine Receptors Mediate Nicotine-Induced Structural Plasticity in Mouse and Human iPSC-Derived Dopaminergic Neurons

“…Constitutive expression of the 6Ld mutation conferred exaggerated behavioral responses to nicotine, high liability to addiction, increased DA release to a nicotine challenge, and induction of functional plasticity phenomena, such an abnormal increase of GluR1 AMPA receptor subunit expression in the VTA DA neurons ( Drenan et al, 2010 ; Berry et al, 2015 ). Genetic association for the risk of developing nicotine dependence was recently confirmed for one polymorphism within the CHRNB3–CHRNA6 gene cluster ( Wen et al, 2016 ). Hypothetically, this liability may become particularly relevant in case an individual carrying some nAChR risk polymorphisms is exposed to nicotine during the last gestational period, as in the case of smoking women during pregnancy.…”

Neurogenetic determinants and mechanisms of addiction to nicotine and smoked tobacco

“…Thus, individuals with genetic variations that result in diminished function of these nAChR subunits may experience less nicotine withdrawal that, in turn, facilitates smoking cessation (Salas et al, 2009;Stoker et al, 2015). Although human studies, in general, do not distinguish affective vs. physical aspects of nicotine withdrawal/dependence, many nAChR subunits (e.g., a2, a3, a5, a6, b3, b4) have been detected in human GWAS for nicotine dependence (Greenbaum & Lerer, 2009;Wen et al, 2016).…”

“…A recent survey by counted a total of 287 human genetics studies on nicotine dependence, including 242 candidate gene association, 22 genome-wide linkage, 18 GWAS, and five targeted sequencing studies. We refer readers to existing reviews for detailed findings (Greenbaum & Lerer, 2009;Wang & Li, 2009;Lassi et al, 2016;Wen et al, 2016). In brief, several neurotransmitter systems, such as the acetylcholinergic, dopaminergic, GABAergic, and glutamatergic systems, have been implicated.…”

Little Evidence of Modified Genetic Effect of rs16969968 on Heavy Smoking Based on Age of Onset of Smoking

“…There is strong evidence from adoption, family, and twin studies that both genetic and environmental factors contribute to risk for smoking behaviors, with heritability estimates for nicotine dependence, ever becoming a regular smoker, and smoking quantity ranging between 33% and 71% [4][5][6][7][8] . Recently, genome-wide association studies (GWAS) have identified common variants associated with smoking behaviors 1,[9][10][11][12][13] . In particular, the nicotinic acetylcholine receptor subunit genes CHRNA5-CHRNA3-CHRNB4 on chromosome 15 have been identified in well-powered GWAS of smoking behaviors 14,15 .…”

“…In particular, the nicotinic acetylcholine receptor subunit genes CHRNA5-CHRNA3-CHRNB4 on chromosome 15 have been identified in well-powered GWAS of smoking behaviors 14,15 . Within CHRNA5, which codes for the α 5 receptor subunit, the nonsynonymous G/A single nucleotide polymorphism (SNP) rs16969968 has been replicated through both large-scale GWAS 1,[9][10][11][12][13]16 and functional assays [17][18][19][20] to influence smoking quantity, as measured by the number of cigarettes smoked per day, and nicotine dependence. The rs16969968-A risk allele has the largest estimated allelic effect on smoking quantity known to date 13 .…”