Smoking Behaviour Phenotypes and Measurement Precision Marcus Munafò

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

Tobacco Dependence Benowitz, N et al. (1982). Clin Pharmacol Ther, 32, 758-764.

Tobacco Dependence Benowitz, N et al. (1982). Clin Pharmacol Ther, 32, 758-764.

Tobacco Dependence

Tobacco Dependence

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

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

GWA Studies of Tobacco Heaviness of smoking shows strong association with 15q25 region Liu et al. (2010). Nat Genet, 42, 436-440.

GWA Studies of Tobacco Liu et al. (2010). Nat Genet, 42, 436-440.

GWA Studies of Tobacco TAG Consortium (2010). Nat Genet, 42, 441-447.

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, 441-447.

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, 448-453.

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

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

Chromosome 15 Jackson et al. (2010). J Pharmacol Exp Ther, 334, 137-146.

Chromosome 15 α5 knockout mice maintain preference (CPP) for nicotine at high doses Jackson et al. (2010). J Pharmacol Exp Ther, 334, 137-146.

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, 1184-1188.

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.

Chromosome 15 Association of rs1051730 with cotinine concentration accounts for ~4% phenotypic variance (compared with ~1% for cigarettes per day) Keskitalo et al. (2009). Hum Mol Med, 18, 4007-4012.

Chromosome 15 Association of rs1051730 / rs16966968 with cotinine level in smokers survives adjustment for self-reported cigarettes per day. Unpublished Data.