Table 2. Multi-method progress made in studying the genetic underpinnings of nicotine addiction.
| Stage of enquiry* | Method | Example |
|---|---|---|
| Phenotyping | Nicotine addiction is a multistage process, with exposure, initiation, regular smoking, heavy smoking, nicotine dependence and persistence.198 Nicotine dependence can be measured using various psychometrically valid assessments (e.g. DSM-IV, FTND, HSI).199 Aspects of nicotine dependence (e.g. FTND—time to first cigarette, DSM-IV withdrawal) contribute to the dependence syndrome while also having features unique to them.200, 201 | |
| Studies of related individuals | Family Studies Twin Studies | 1.77 increased hazards of habitual smoking in relatives of smokers.202 Cigarette smoking is heritable.203 Genetic factors influence smoking initiation (75%), quantity smoked (57%), nicotine dependence (60%), persistence (40–50%) and nicotine withdrawal (40%). There is significant overlap of genetic influences between smoking initiation and nicotine dependence as well as persistence.7 Dependence measures using HSI/FTND are more heritable than DSM-IV.8 19% of genetic influences on DSM-IV withdrawal do not overlap with other aspects of smoking.204 |
| Gene finding | Linkage | Several linkage studies of smoking behaviors. A recent meta-analysis implicates 17q24.3–q25.3 with regions on 17q24.3–q25.3, 20p12.1–q13.12, 20q13.12–q13.32 and 22q12.3–q13.32 significant or suggestive for maximum cigarettes smoked in a 24-h period.205 |
| Candidate genes | The nicotinic acetylcholine receptor subunit genes, including CHRNA5/A3/B4 (chr 15), CHRNA4 (chr 20), CHRNB2 (chr 1), as well as CYP2A6 (chr 19), OPRM1 (chr 6) and DRD2/ANKK1 (chr 11) have been actively studied. | |
| GWAS | Most widely replicated GWAS signal, first identified via candidate gene analysis,91 is a missense mutation, rs16969968 (D398N, or proxy, rs1051730) in the CHRNA5/A3/B4 cluster. Subsequent meta-analysis identified it at P<10−70.88, 89, 90 | |
| Gene–environment interplay | Latent genetic/twin | Heritable influences on adolescent smoking increase with decreasing parental monitoring.150 Heritable influences on onset and daily smoking decrease with increasing state-level taxation, control and policy stringency.206 |
| Measured genetic/SNP | Those with high-risk genotype of rs16969968 are less sensitive to peer influences207 although the effect of the risk variant is most pronounced in those exposed to low parental monitoring.208 Age at onset of smoking behaviors interacts with rs16969968 to predict continued smoking, although studies diverge on whether the variant exerts greater influence in early or late onset smokers.209, 210 | |
| Biological relevance | Bioinformatics | Pathway analyses reveal that genes in glutamatergic, tyrosine kinase signaling, transporter, cell adhesion and opioidergic systems influence smoking.211 |
| Biological function via experiments | Mice homozygous for absence of α5 subunit (−/−) show reduced sensitivity to a variety of physiological outcomes associated with nicotine or its agonists.212 Increased nicotine intake in α5 knock-out mice, which is rescued by re-expressing α5 in the medial habenula.213 Epibatidine response is nearly twice as high for cells transfected with wild-type (D398) relative to the N398 variant but there were no differences in receptor expression.195 Greater short-term desensitization of N398-containing receptors has been noted but only when coupled with α4β2 subunits.196 | |
| Neuroimaging | rs16969968 associated with reduced functional connectivity between dorsal anterior cingulate cortex ventral striatum and extended amygdala. Those with low risk variant show increased response to smoking cues in the brain regions linked to memory and habitual behaviors.214 | |
| Treatment | Pharmacogenomics | Minor allele carriers of CHRNB2 variants experience greater nausea and dizziness upon use of varencline.215 High (42 mg) nicotine dose more efficacious in highly dependent smokers with a low quit-success genotype score based on 12,508 SNPs216 |
Abbreviations; DSM, Diagnostic and Statistical Manual of Mental Disorders; FTND, Fagerstrom Test for Nicotine Dependence; GWAS, genomewide association study; HSI, Heaviness of Smoking Index; SNP, single nucleotide polymorphism.