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.

Keywords: CHRNA5–A3–B4; phenotype definition; precision medicine; smoking behaviour; tobacco-related disorders.

Figure 1

Key Figure: From Nicotine Consumption to Personalised Intervention through Genetic Studies (A) Hypothesis-free studies. Manhattan plot showing findings of a genome-wide association study (GWAS) that looked at heaviness of smoking measured as cigarettes per day (CPD) and associated genetic signals. SNPs are plotted on the x-axis according to their position on the chromosome, against the phenotype on the y-axis shown as −log¹⁰P value. The strongest association with smoking quantity was found for the SNP rs1051730, followed by rs16969968. GWASs are free from a priori hypotheses. Reprinted by permission from Macmillan Publishers Ltd on behalf of Cancer Research UK: Nature Genetics 42(5), 441–447, copyright 2010. (B) Hypothesis-driven studies. Investigations with a specific genetic target follow GWASs and previous investigations and employ strategies such as recall by genotype and Mendelian randomisation (MR). The graph represents the distribution of the population (European ancestry) according to their phenotype (on the x-axis). Homozygous individuals – wild type in yellow on the left and biallelic carriers of the risk allele in red on the right – reside at its ends. (C) Neurobiology of smoking behaviour. Schematic drawing of the journey of cigarette smoke through the airways to the lungs, the bloodstream, and, eventually, the brain. (D) Precise therapeutic intervention. Here is shown a possible intervention to selectively address individuals with nicotinic acetylcholine receptors (nAChRs) comprising a D398N α5 subunit (encoded by the minor allele). A specific agonist binds to the receptor and enhances its trafficking of ions (Ca⁺⁺, Na⁺, and K⁺).

Figure 2

The Genetic Locus CHRNA5–CHRNA3–CHRNB4 Encodes the Subunits of a Nicotinic Acetylcholine Receptor (nAChR). (A) Simplified illustration of the human CHRNA5–CHRNA3–CHRNB4 gene cluster, which encodes the α3, α5, and β4 nAChR subunits (not to scale). CHRNA5 is marked by rs16969968, which is in high linkage disequilibrium with rs1051730 in CHRNA3. (B) Subunit composition of the heteromeric α5–α3–β4 nAChR. Nicotine is an exogenous ligand for nAChRs; when nicotine binds to a nAChR, it modulates its trafficking of cations.

Figure 3

Mendelian Randomisation Using rs16969968 in CHRNA5 as an Instrument for Smoking Heaviness. (A) In Mendelian randomisation analyses, rs16969968 is used as a proxy for smoking heaviness in ever-smokers. While the association between smoking heaviness (e.g., number of cigarettes smoked per day) and the outcome of interest may be confounded by lifestyle and demographic factors (e.g., diet), the association between rs16969968 and the outcome should not be. The outcome of interest may influence smoking heaviness (reverse causality) but will not influence rs16969968 genotype. (B) As never-smokers do not smoke, any association between genotype and outcome cannot be operating through effects of the genotype on smoking.