Genome-wide and candidate gene association study of cigarette smoking behaviors

Neil Caporaso, Fangyi Gu, Nilanjan Chatterjee, Jin Sheng-Chih, Kai Yu, Meredith Yeager, Constance Chen, Kevin Jacobs, William Wheeler, Maria Teresa Landi, Regina G Ziegler, David J Hunter, Stephen Chanock, Susan Hankinson, Peter Kraft, Andrew W Bergen, Neil Caporaso, Fangyi Gu, Nilanjan Chatterjee, Jin Sheng-Chih, Kai Yu, Meredith Yeager, Constance Chen, Kevin Jacobs, William Wheeler, Maria Teresa Landi, Regina G Ziegler, David J Hunter, Stephen Chanock, Susan Hankinson, Peter Kraft, Andrew W Bergen

Abstract

The contribution of common genetic variation to one or more established smoking behaviors was investigated in a joint analysis of two genome wide association studies (GWAS) performed as part of the Cancer Genetic Markers of Susceptibility (CGEMS) project in 2,329 men from the Prostate, Lung, Colon and Ovarian (PLCO) Trial, and 2,282 women from the Nurses' Health Study (NHS). We analyzed seven measures of smoking behavior, four continuous (cigarettes per day [CPD], age at initiation of smoking, duration of smoking, and pack years), and three binary (ever versus never smoking, < or = 10 versus > 10 cigarettes per day [CPDBI], and current versus former smoking). Association testing for each single nucleotide polymorphism (SNP) was conducted by study and adjusted for age, cohabitation/marital status, education, site, and principal components of population substructure. None of the SNPs achieved genome-wide significance (p<10(-7)) in any combined analysis pooling evidence for association across the two studies; we observed between two and seven SNPs with p<10(-5) for each of the seven measures. In the chr15q25.1 region spanning the nicotinic receptors CHRNA3 and CHRNA5, we identified multiple SNPs associated with CPD (p<10(-3)), including rs1051730, which has been associated with nicotine dependence, smoking intensity and lung cancer risk. In parallel, we selected 11,199 SNPs drawn from 359 a priori candidate genes and performed individual-gene and gene-group analyses. After adjusting for multiple tests conducted within each gene, we identified between two and five genes associated with each measure of smoking behavior. Besides CHRNA3 and CHRNA5, MAOA was associated with CPDBI (gene-level p<5.4x10(-5)), our analysis provides independent replication of the association between the chr15q25.1 region and smoking intensity and data for multiple other loci associated with smoking behavior that merit further follow-up.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. −log 10 p-values for association…
Figure 1. −log10 p-values for association with seven continuous (Figure 1) and categorical (Figure 2) smoking behaviors.
P-values are based on the combined evidence for association from both PLCO and NHS.
Figure 2. −log 10 p-values for association…
Figure 2. −log10 p-values for association with seven continuous (Figure 1) and categorical (Figure 2) smoking behaviors.
P-values are based on the combined evidence for association from both PLCO and NHS.
Figure 3. −log 10 p-values for association…
Figure 3. −log10 p-values for association with number of cigarettes smoked per day (CPD) for SNPs in the chr15q25.1 region.
P-values are based on the combined evidence for association from both PLCO and NHS. Filled symbols denote genotyped SNPs; open symbols denote imputed SNPs. Black diamonds (squares) denote SNPs associated with continuous (binary) CPD in previous reports. Red circles denote SNPs associated with lung cancer in previous reports.

References

    1. Bergen AW, Caporaso N. Cigarette smoking. J Natl Cancer Inst. 1999;91:1365–1375.
    1. Ronald M, Davis TEN, Willaim RLynn, editors. The Health Consequences of Smoking: Nicotine Addiction: A Report of the Surgeon General: Center for Health Promotion and Education, Office on Smoking and Health, United States Public Health Service, Office of the Surgeon General 1988
    1. Batra V, Patkar AA, Berrettini WH, Weinstein SP, Leone FT. The genetic determinants of smoking. Chest. 2003;123:1730–1739.
    1. Li MD. The genetics of nicotine dependence. Curr Psychiatry Rep. 2006;8:158–164.
    1. Maes HH, Sullivan PF, Bulik CM, Neale MC, Prescott CA, et al. A twin study of genetic and environmental influences on tobacco initiation, regular tobacco use and nicotine dependence. Psychol Med. 2004;34:1251–1261.
    1. Lessov CN, Martin NG, Statham DJ, Todorov AA, Slutske WS, et al. Defining nicotine dependence for genetic research: evidence from Australian twins. Psychol Med. 2004;34:865–879.
    1. Vink JM, Beem AL, Posthuma D, Neale MC, Willemsen G, et al. Linkage analysis of smoking initiation and quantity in Dutch sibling pairs. Pharmacogenomics J. 2004;4:274–282.
    1. Vink JM, Posthuma D, Neale MC, Eline Slagboom P, Boomsma DI. Genome-wide linkage scan to identify Loci for age at first cigarette in Dutch sibling pairs. Behav Genet. 2006;36:100–111.
    1. Bergen AW, Korczak JF, Weissbecker KA, Goldstein AM. A genome-wide search for loci contributing to smoking and alcoholism. Genet Epidemiol. 1999;17(Suppl 1):S55–60.
    1. Lessov-Schlaggar CN, Pergadia ML, Khroyan TV, Swan GE. Genetics of nicotine dependence and pharmacotherapy. Biochem Pharmacol. 2008;75:178–195.
    1. Swan GE, Hops H, Wilhelmsen KC, Lessov-Schlaggar CN, Cheng LS, et al. A genome-wide screen for nicotine dependence susceptibility loci. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:354–360.
    1. Li MD, Ma JZ, Payne TJ, Lou XY, Zhang D, et al. Genome-wide linkage scan for nicotine dependence in European Americans and its converging results with African Americans in the Mid-South Tobacco Family sample. Mol Psychiatry. 2008;13:407–416.
    1. Li MD, Payne TJ, Ma JZ, Lou XY, Zhang D, et al. A genomewide search finds major susceptibility loci for nicotine dependence on chromosome 10 in African Americans. Am J Hum Genet. 2006;79:745–751.
    1. Sullivan PF, Neale BM, van den Oord E, Miles MF, Neale MC, et al. Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics. Am J Med Genet B Neuropsychiatr Genet. 2004;126B:23–36.
    1. Moslehi R, Goldstein AM, Beerman M, Goldin L, Bergen AW. A genome-wide linkage scan for body mass index on Framingham Heart Study families. BMC Genet. 2003;4(Suppl 1):S97.
    1. Saccone SF, Pergadia ML, Loukola A, Broms U, Montgomery GW, et al. Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples. Am J Hum Genet. 2007;80:856–866.
    1. Gelernter J, Liu X, Hesselbrock V, Page GP, Goddard A, et al. Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking. Am J Med Genet B Neuropsychiatr Genet. 2004;128B:94–101.
    1. Bierut LJ, Rice JP, Goate A, Hinrichs AL, Saccone NL, et al. A genomic scan for habitual smoking in families of alcoholics: common and specific genetic factors in substance dependence. Am J Med Genet A. 2004;124:19–27.
    1. Ehlers CL, Wilhelmsen KC. Genomic screen for loci associated with tobacco usage in Mission Indians. BMC Med Genet. 2006;7:9.
    1. Pomerleau OF, Pomerleau CS, Chu J, Kardia SL. Genome-wide linkage analysis for smoking-related regions, with replication in two ethnically diverse populations. Nicotine Tob Res. 2007;9:955–958.
    1. Li MD. The genetics of smoking related behavior: a brief review. Am J Med Sci. 2003;326:168–173.
    1. Li MD, Sun D, Lou XY, Beuten J, Payne TJ, et al. Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence. Mol Psychiatry. 2007;12:462–473.
    1. Faraone SV, Su J, Taylor L, Wilcox M, Van Eerdewegh P, et al. A novel permutation testing method implicates sixteen nicotinic acetylcholine receptor genes as risk factors for smoking in schizophrenia families. Hum Hered. 2004;57:59–68.
    1. Li MD. Identifying susceptibility loci for nicotine dependence: 2008 update based on recent genome-wide linkage analyses. Hum Genet. 2008;123:119–131.
    1. Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, et al. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. J Psychoactive Drugs. 2000;32(Suppl):1–112.
    1. Blum K, Sheridan PJ, Wood RC, Braverman ER, Chen TJ, et al. The D2 dopamine receptor gene as a determinant of reward deficiency syndrome. J R Soc Med. 1996;89:396–400.
    1. Comings DE, Blum K. Reward deficiency syndrome: genetic aspects of behavioral disorders. Prog Brain Res. 2000;126:325–341.
    1. Lerman C, Wileyto EP, Patterson F, Rukstalis M, Audrain-McGovern J, et al. The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial. Pharmacogenomics J. 2004;4:184–192.
    1. Ray R, Jepson C, Wileyto EP, Dahl JP, Patterson F, et al. Genetic variation in mu-opioid-receptor-interacting proteins and smoking cessation in a nicotine replacement therapy trial. Nicotine Tob Res. 2007;9:1237–1241.
    1. Lerman C, Caporaso NE, Audrain J, Main D, Boyd NR, et al. Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence. Mol Psychiatry. 2000;5:189–192.
    1. Lerman C, Shields PG, Audrain J, Main D, Cobb B, et al. The role of the serotonin transporter gene in cigarette smoking. Cancer Epidemiol Biomarkers Prev. 1998;7:253–255.
    1. O'Gara C, Knight J, Stapleton J, Luty J, Neale B, et al. Association of the serotonin transporter gene, neuroticism and smoking behaviours. J Hum Genet. 2008;53:239–246.
    1. Blum K, Sheridan PJ, Wood RC, Braverman ER, Chen TJ, et al. Dopamine D2 receptor gene variants: association and linkage studies in impulsive-addictive-compulsive behaviour. Pharmacogenetics. 1995;5:121–141.
    1. McKinney EF, Walton RT, Yudkin P, Fuller A, Haldar NA, et al. Association between polymorphisms in dopamine metabolic enzymes and tobacco consumption in smokers. Pharmacogenetics. 2000;10:483–491.
    1. Shields PG, Lerman C, Audrain J, Bowman ED, Main D, et al. Dopamine D4 receptors and the risk of cigarette smoking in African-Americans and Caucasians. Cancer Epidemiol Biomarkers Prev. 1998;7:453–458.
    1. Benowitz NL, Swan GE, Jacob P, 3rd, Lessov-Schlaggar CN, Tyndale RF. CYP2A6 genotype and the metabolism and disposition kinetics of nicotine. Clin Pharmacol Ther. 2006;80:457–467.
    1. Caporaso NE, Lerman C, Audrain J, Boyd NR, Main D, et al. Nicotine metabolism and CYP2D6 phenotype in smokers. Cancer Epidemiol Biomarkers Prev. 2001;10:261–263.
    1. Fujieda M, Yamazaki H, Saito T, Kiyotani K, Gyamfi MA, et al. Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male Japanese smokers. Carcinogenesis. 2004;25:2451–2458.
    1. Kamataki T, Fujieda M, Kiyotani K, Iwano S, Kunitoh H. Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk. Biochem Biophys Res Commun. 2005;338:306–310.
    1. Malaiyandi V, Sellers EM, Tyndale RF. Implications of CYP2A6 genetic variation for smoking behaviors and nicotine dependence. Clin Pharmacol Ther. 2005;77:145–158.
    1. Strasser AA, Malaiyandi V, Hoffmann E, Tyndale RF, Lerman C. An association of CYP2A6 genotype and smoking topography. Nicotine Tob Res. 2007;9:511–518.
    1. Li MD, Beuten J, Ma JZ, Payne TJ, Lou XY, et al. Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) with nicotine dependence. Hum Mol Genet. 2005;14:1211–1219.
    1. Lou XY, Ma JZ, Payne TJ, Beuten J, Crew KM, et al. Gene-based analysis suggests association of the nicotinic acetylcholine receptor beta1 subunit (CHRNB1) and M1 muscarinic acetylcholine receptor (CHRM1) with vulnerability for nicotine dependence. Hum Genet. 2006;120:381–389.
    1. Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature. 2008;452:638–642.
    1. Berrettini W, Yuan X, Tozzi F, Song K, Francks C, et al. Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry. 2008;13:368–373.
    1. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet. 2008;40:616–622.
    1. Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 2008;452:633–637.
    1. Chanock SJ, Hunter DJ. Genomics: when the smoke clears. Nature. 2008;452:537–538.
    1. Weiss RB, Baker TB, Cannon DS, von Niederhausern A, Dunn DM, et al. A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS Genet. 2008;4:e1000125.
    1. Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, et al. Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet. 2007;16:36–49.
    1. Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007;39:870–874.
    1. Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet. 2007;39:645–649.
    1. Pritchard JK, Rosenberg NA. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet. 1999;65:220–228.
    1. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38:904–909.
    1. Prorok PC, Andriole GL, Bresalier RS, Buys SS, Chia D, et al. Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials. 2000;21:273S–309S.
    1. Whitlock G, Lewington S, Mhurchu CN. Coronary heart disease and body mass index: a systematic review of the evidence from larger prospective cohort studies. Semin Vasc Med. 2002;2:369–381.
    1. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558.
    1. Gauderman WJ, Morrison JL, Siegmund KD. Should we consider gene x environment interaction in the hunt for quantitative trait loci? Genet Epidemiol. 2001;21(Suppl 1):S831–836.
    1. Bierut LJ, Madden PA, Breslau N, Johnson EO, Hatsukami D, et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet. 2007;16:24–35.
    1. Dudbridge F, Koeleman BP. Rank truncated product of P-values, with application to genomewide association scans. Genet Epidemiol. 2003;25:360–366.
    1. Wang K, Li M, Bucan M. Pathway-Based Approaches for Analysis of Genomewide Association Studies. Am J Hum Genet. 2007;81
    1. Li M, Atmaca-Sonmez P, Othman M, Branham KE, Khanna R, et al. CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration. Nat Genet. 2006;38:1049–1054.
    1. Li MD, Cheng R, Ma JZ, Swan GE. A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction. 2003;98:23–31.
    1. Kenfield SA, Stampfer MJ, Rosner BA, Colditz GA. Smoking and smoking cessation in relation to mortality in women. Jama. 2008;299:2037–2047.
    1. Lubin JH, Caporaso N, Hatsukami DK, Joseph AM, Hecht SS. The association of a tobacco-specific biomarker and cigarette consumption and its dependence on host characteristics. Cancer Epidemiol Biomarkers Prev. 2007;16:1852–1857.
    1. Munafo MR, Johnstone EC. Genes and cigarette smoking. Addiction. 2008;103:893–904.
    1. Fowler JS, Logan J, Wang GJ, Volkow ND. Monoamine oxidase and cigarette smoking. Neurotoxicology. 2003;24:75–82.
    1. Fowler JS, Logan J, Wang GJ, Volkow ND, Telang F, et al. Comparison of monoamine oxidase a in peripheral organs in nonsmokers and smokers. J Nucl Med. 2005;46:1414–1420.
    1. Saccone NL, Rice JP, Rochberg N, Williams JT, Goate A, et al. Linkage for platelet monoamine oxidase (MAO) activity: results from a replication sample. Alcohol Clin Exp Res. 2002;26:603–609.
    1. Wiesbeck GA, Wodarz N, Weijers HG, Dursteler-MacFarland KM, Wurst FM, et al. A functional polymorphism in the promoter region of the monoamine oxidase A gene is associated with the cigarette smoking quantity in alcohol-dependent heavy smokers. Neuropsychobiology. 2006;53:181–185.
    1. Checkoway H, Franklin GM, Costa-Mallen P, Smith-Weller T, Dilley J, et al. A genetic polymorphism of MAO-B modifies the association of cigarette smoking and Parkinson's disease. Neurology. 1998;50:1458–1461.
    1. Ragonese P, Salemi G, Morgante L, Aridon P, Epifanio A, et al. A case-control study on cigarette, alcohol, and coffee consumption preceding Parkinson's disease. Neuroepidemiology. 2003;22:297–304.
    1. Tan EK, Chai A, Lum SY, Shen H, Tan C, et al. Monoamine oxidase B polymorphism, cigarette smoking and risk of Parkinson's disease: a study in an Asian population. Am J Med Genet B Neuropsychiatr Genet. 2003;120B:58–62.
    1. Ito H, Hamajima N, Matsuo K, Okuma K, Sato S, et al. Monoamine oxidase polymorphisms and smoking behaviour in Japanese. Pharmacogenetics. 2003;13:73–79.
    1. Jin Y, Chen D, Hu Y, Guo S, Sun H, et al. Association between monoamine oxidase gene polymorphisms and smoking behaviour in Chinese males. Int J Neuropsychopharmacol. 2006;9:557–564.
    1. Lewis A, Miller JH, Lea RA. Monoamine oxidase and tobacco dependence. Neurotoxicology. 2007;28:182–195.
    1. Tochigi M, Suzuki K, Kato C, Otowa T, Hibino H, et al. Association study of monoamine oxidase and catechol-O-methyltransferase genes with smoking behavior. Pharmacogenet Genomics. 2007;17:867–872.
    1. Nilius B, Owsianik G, Voets T, Peters JA. Transient receptor potential cation channels in disease. Physiol Rev. 2007;87:165–217.
    1. Feng Z, Li W, Ward A, Piggott BJ, Larkspur ER, et al. A C. elegans model of nicotine-dependent behavior: regulation by TRP-family channels. Cell. 2006;127:621–633.
    1. Gu Q, Lin RL, Hu HZ, Zhu MX, Lee LY. 2-aminoethoxydiphenyl borate stimulates pulmonary C neurons via the activation of TRPV channels. Am J Physiol Lung Cell Mol Physiol. 2005;288:L932–941.
    1. Mwenifumbo JC, Tyndale RF. Genetic variability in CYP2A6 and the pharmacokinetics of nicotine. Pharmacogenomics. 2007;8:1385–1402.
    1. Nakajima M. Smoking behavior and related cancers: the role of CYP2A6 polymorphisms. Curr Opin Mol Ther. 2007;9:538–544.
    1. Haberl M, Anwald B, Klein K, Weil R, Fuss C, et al. Three haplotypes associated with CYP2A6 phenotypes in Caucasians. Pharmacogenet Genomics. 2005;15:609–624.
    1. Tyndale RF, Sellers EM. Genetic variation in CYP2A6-mediated nicotine metabolism alters smoking behavior. Ther Drug Monit. 2002;24:163–171.
    1. Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, et al. Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev. 2004;18:2573–2580.
    1. Rezvani K, Teng Y, Shim D, De Biasi M. Nicotine regulates multiple synaptic proteins by inhibiting proteasomal activity. J Neurosci. 2007;27:10508–10519.
    1. Caporaso NE. Integrative study designs–next step in the evolution of molecular epidemiology? Cancer Epidemiol Biomarkers Prev. 2007;16:365–366.
    1. Seminara D, Khoury MJ, O'Brien TR, Manolio T, Gwinn ML, et al. The emergence of networks in human genome epidemiology: challenges and opportunities. Epidemiology. 2007;18:1–8.
    1. Rebbeck TR, Spitz M, Wu X. Assessing the function of genetic variants in candidate gene association studies. Nat Rev Genet. 2004;5:589–597.

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