1. Smoking Behaviour Phenotypes and Measurement Precision
Marcus Munafò

2. Tobacco Dependence
Cigarettes and other tobacco products have addiction liability largely due to nicotine content
Nicotine presented as a discrete bolus, and rapidly transferred to the brain (10-20 sec) when smoked
Delivered frequently and repetitively, and in the context of multiple cues

3. Tobacco Dependence
Benowitz, N et al. (1982). Clin Pharmacol Ther, 32,

4. Tobacco Dependence
Benowitz, N et al. (1982). Clin Pharmacol Ther, 32,

5. Tobacco Dependence

6. Tobacco Dependence

7. Candidate Gene Studies
Dopamine
Noradrenaline
Acetylcholine
Serotonin
Glutamate
NICOTINE
Vasopressin
GABA
80%
COTININE

8. Candidate Gene Studies
DRD2
DBH
DRD4
MAO
COMT
MAO
COMT
Dopamine
Noradrenaline
Acetylcholine
5HT1A
SLC6A4
MAO
Serotonin
Glutamate
NICOTINE
Vasopressin
GABA
CYP2A6
CYP2B6
80%
COTININE

9. GWA Studies of Tobacco
Heaviness of smoking shows strong association with 15q25 region
Liu et al. (2010). Nat Genet, 42,

10. GWA Studies of Tobacco
Liu et al. (2010). Nat Genet, 42,

11. GWA Studies of Tobacco
TAG Consortium (2010). Nat Genet, 42,

12. GWA Studies of Tobacco
SNPs in BDNF associated with smoking initiation (ever vs never), and in DBH with smoking cessation (former vs current)
TAG Consortium (2010). Nat Genet, 42,

13. GWA Studies of Tobacco
SNPs in 15q25, 19q13, 8p11 and 7p14 show association with heaviness of smoking (cigarettes per day)
Thorgeirsson et al. (2010). Nat Genet, 42,

14. GWA Studies of Tobacco
GWA studies have been successful in identifying SNPs associated with various tobacco use phenotypes
The number of individual genes identified, and % phenotypic variance explained, remains modest

15. GWA Studies of Tobacco
Identification of novel genes implicated in tobacco use (e.g., CHRNA5) has led to renewed interest in these gene products
Phenotypes employed in GWA studies are necessarily crude, often relying on retrospective self-report

16. Chromosome 15
Jackson et al. (2010). J Pharmacol Exp Ther, 334,

17. Chromosome 15
α5 knockout mice maintain preference (CPP) for nicotine at high doses
Jackson et al. (2010). J Pharmacol Exp Ther, 334,

18. Chromosome 15
Serum Cotinine OR
95% CI
1 – 28
1.00
Reference
29 – 140
0.93
0.46, 1.90
141 – 651
2.80
1.55, 5.05
652 – 1024
7.76
4.75, 12.40
1024 – 1271
13.80
8.70, 22.00
1272 – 1544
24.90
15.90, 39.00
1545 – 1805
30.40
19.50, 47.30
1805 – 2152
33.10
21.30, 51.40
> 2152
55.10
35.70, 85.00
Association of serum cotinine with risk of lung cancer shows stronger association than with cigarettes per day
Boffetta et al. (2006). Cancer Epi Biomarkers Prev, 15,

19. Chromosome 15
Measures of nicotine / tar content, and number of cigarettes per day, correlate poorly with tobacco-specific nitrosamine exposure (top panel) due to compensatory smoking (bottom panel)
Unpublished Data.

20. Chromosome 15
Association of rs with cotinine concentration accounts for ~4% phenotypic variance (compared with ~1% for cigarettes per day)
Keskitalo et al. (2009). Hum Mol Med, 18,

21. Chromosome 15
Association of rs / rs with cotinine level in smokers survives adjustment for self-reported cigarettes per day.
Unpublished Data.