The CHRNA5–A3–B4 Gene Cluster and Smoking: From Discovery to Therapeutics

Abstract

Genome-wide association studies (GWASs) have identified associations between the CHRNA5–CHRNA3–CHRNB4 gene cluster and smoking heaviness and nicotine dependence. Studies in rodents have described the anatomical localisation and function of the nicotinic acetylcholine receptors (nAChRs) formed by the subunits encoded by this gene cluster. Further investigations that complemented these studies highlighted the variability of individuals’ smoking behaviours and their ability to adjust nicotine intake. GWASs of smoking-related health outcomes have also identified this signal in the CHRNA5–CHRNA3–CHRNB4 gene cluster. This insight underpins approaches to strengthen causal inference in observational data. Combining genetic and mechanistic studies of nicotine dependence and smoking heaviness may reveal novel targets for medication development. Validated targets can inform genetic therapeutic interventions for smoking cessation and tobacco-related diseases.

Gene-Gene interactions and pleiotropy in the brain nicotinic pathway associated with the heaviness and precocity of tobacco smoking among outpatients with multiple substance use disorders

“…To conclude, the present study provides multiple-level, yet preliminary evidence that, in people at high-risk for severe smoking outcomes, gene variants from the nicotinic pathway may further moderate the risk for specific tobacco smoking phenotypes. Associations showed both a polygenic and a pleiotropic nature that included SNP x SNP interactions, in line with previous research in less specific populations [14]. Taken altogether, our findings also highlight the importance of metabolic and chaperone/trafficking proteins in the pathogenicity of nAChRs.…”

“…The present study replicated the previously identified associations between CHRNA3 and smoking behaviours, including the number of CPD, which typically involved rs1051730 [14], a plausible tag marker for functional haplotypes in the CHRNA5-A3-B4 cluster. This makes rs8040868 a relatively new SNP of interest in the cluster.…”

“…Finally, pleiotropy, i.e. simultaneous associations between a given gene or SNP with several smoking phenotypes is expected [14], as in most complex traits [15].…”

Neurogenetic determinants and mechanisms of addiction to nicotine and smoked tobacco

“…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.…”

Specific connections of the interpeduncular subnuclei reveal distinct components of the habenulopeduncular pathway

“…The vMHb/IP pathway is also of interest due to its expression of unusual acetylcholine receptor subunits, including the channel‐forming α3 and β4 receptor subunits in the vMHb, and the “accessory” α5 receptor subunit expressed in the IP subnuclei that receive vMHb input (Hsu et al, ; Marks et al, ; Salas et al, ). These nicotinic receptors are of special interest because the genes encoding the α5/α3/β4 subunits are colocated in the mouse and human genomes, and in humans, alleles at this locus, including a functional variant in the α5 receptor, have been associated with smoking behavior (Berrettini & Doyle, ; Lassi et al, ).…”