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PLOS ONE  2012 

Haplotypes with Copy Number and Single Nucleotide Polymorphisms in CYP2A6 Locus Are Associated with Smoking Quantity in a Japanese Population

DOI: 10.1371/journal.pone.0044507

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Smoking is a major public health problem, but the genetic factors associated with smoking behaviors are not fully elucidated. Here, we have conducted an integrated genome-wide association study to identify common copy number polymorphisms (CNPs) and single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) in Japanese smokers ( = 17,158). Our analysis identified a common CNP with a strong effect on CPD (rs8102683; ) in the 19q13 region, encompassing the CYP2A6 locus. After adjustment for the associated CNP, we found an additional associated SNP (rs11878604; ) located 30 kb downstream of the CYP2A6 gene. Imputation of the CYP2A6 locus revealed that haplotypes underlying the CNP and the SNP corresponded to classical, functional alleles of CYP2A6 gene that regulate nicotine metabolism and explained 2% of the phenotypic variance of CPD (ANOVA -test ). These haplotypes were also associated with smoking-related diseases, including lung cancer, chronic obstructive pulmonary disease and arteriosclerosis obliterans.


[1]  Ikeda F, Ninomiya T, Doi Y, Hata J, Fukuhara M, et al.. (2011) Smoking cessation improves mortality in japanese men: the hisayama study. Tob Control. : Published Online First.
[2]  Li MD, Cheng R, Ma JZ, Swan GE (2003) A meta-analysis of estimated genetic and environmental effects on smoking behavior in male and female adult twins. Addiction. 98: 23–31.
[3]  Koopmans JR, Slutske WS, Heath AC, Neale MC, Boomsma DI (1999) The genetics of smoking initiation and quantity smoked in dutch adolescent and young adult twins. Behav Genet. 29: 383–93.
[4]  Thorgeirsson TE, Gudbjartsson DF, Surakka I, Vink JM, Amin N, et al. (2010) Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior. Nat Genet. 42: 448–53.
[5]  Liu JZ, Tozzi F, Waterworth DM, Pillai SG, Muglia P, et al. (2010) Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat Genet. 42: 436–40.
[6]  Tobacco and Genetics Consortium (2010) Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat Genet. 42: 441–7.
[7]  Nakamura Y (2007) The biobank japan project. Clin. Adv. Hematol. Oncol. 5: 696–7.
[8]  Kumasaka N, Fujisawa N, Hosono N, Okada Y, Takahashi A, et al. (2011) PlatinumCNV: a Bayesian Gaussian mixture model for genotyping copy number polymorphisms using SNP array signal intensity data. Genet. Epidemiol. 35: 831–844.
[9]  Okada Y, Hirota T, Kamatani Y, Takahashi A, Ohmiya H, et al. (2011) Identification of nine novel loci associated with white blood cell subtypes in a Japanese population. PLoS Genet. 7: e1002067.
[10]  Devlin B, Roeder K (1999) Genomic control for association studies. Biometrics 55: 997–1004.
[11]  Plagnol V, Cooper JD, Todd JA, Clayton DG (2007) A method to address differential bias in genotyping in large-scale association studies. PLoS Genet. 3: e74.
[12]  Fujieda M, Yamazaki H, Saito T, Kiyotani K, Gyamfi MA, et al. (2004) Evaluation of CYP2A6 genetic polymorphisms as determinants of smoking behavior and tobacco-related lung cancer risk in male japanese smokers. Pharmacogenet. Genomics. 25: 2451–8.
[13]  Swan GE, Benowitz NL, Lessov CN, Jacov P, Tyndale RF, et al. (2005) Nicotine metabolism; the impact of CYP2A6 on estimates of additive genetic influence. Carcinogenesis 15: 115–25.
[14]  Schoedel KA, Hoffmann EB, Rao Y, Sellers EM, Tyndale RF (2004) Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult caucasians. Pharmacogenetics 14: 615–26.
[15]  Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, et al. (2009) Finding the missing heritability of complex diseases. Nature. 461: 747–53.
[16]  Girirajan S, Campbell CD, Eichler EE (2011) Human copy number variation and complex genetic disease. Annu. Rev. Genet. 45: 203–26.
[17]  Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, et al. (2010) Origins and functional impact of copy number variation in the human genome. Nature. 464: 704–12.
[18]  Wellcome Trust Case Control Consortium (2010) Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 464: 713–20.
[19]  Li B, Leal SM (2008) Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet 83: 311–21.
[20]  Madsen BE, Browning SR (2009) A groupwise association test for rare mutations using a weighted sum statistic. PLoS Genet 5: e1000384.
[21]  Liu DJ, Leal SM (2010) A novel adaptive method for the analysis of next-generation sequencing data to detect complex trait associations with rare variants due to gene main effects and interactions. PLoS Genet 6: e1001156.
[22]  Morris AP, Zeggini E (2010) An evaluation of statistical approaches to rare variant analysis in genetic association studies. Genet Epidemiol 34: 188–93.
[23]  Sabeti PC, Schaffner SF, Fry B, Lohmueller J, Varilly P, et al. (2006) Positive natural selection in the human lineage. Science 312: 1614–1620.
[24]  Hosono N, Kato M, Kiyotani K, Mushiroda T, Takata S, et al. (2009) CYP2D6 genotyping for functional-gene dosage analysis by allele copy number detection. Clinical Chemistry. 55: 1546–54.
[25]  Bodin L, Beaune PH, Loriot MA (2005) Determination of cytochrome P450 2D6 (CYP2D6) gene copy number by real-time quantitative pcr. J. Biomed. Biotechnol. 3: 248–253.
[26]  Kumasaka N, Yamaguchi-Kabata Y, Takahashi A, Kubo M, Nakamura Y, et al. (2010) Establishment of a standardized system to perform population structure analyses with limited sample size or with different sets of snp genotypes. Journal of Human Genetics 55: 525–33.
[27]  Stram DO, Pearce CL, Bretsky P, Freedman M, Hirschhorn JN, et al. (2003) Modeling and E-M estimation of haplotype-specific relative risks from genotype data for a case-control study of unrelated individuals. Hum. Hered. 55: 179–90.
[28]  McLachlan GJ, Krishman T (1997) The EM Algorithm and Extensions. New York: John Wiley & Sons.
[29]  Dempster ER, Lerner IM (1950) Heritability of threshold characters. Genetics 35: 212–236.
[30]  McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, et al. (2010) The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20: 1297–1303.
[31]  Barnes CA, Plagnol V, Fitzgerald T, Redon R, Marchini J, et al. (2008) Robust statistical method for case-control association testing with copy number variation. Nat. Genet. 40: 1245–52.
[32]  Baum LE, Petrie T, Soules G, Weiss N (1970) A maximization technique occurring in the statistical analysis of probabilistic functions of Markov chains. Ann. Math. Statist. 41: 164–71.
[33]  Browning BL, Browning SR (2009) A unified approach to genotype imputation and haplotypephase inference for large data sets of trios and unrelated individuals. Am. J. Hum. Genet. 84: 210–23.
[34]  Korn JM, Kuruvilla FG, McCarroll SA, Wysoker A, Nemesh J, et al. (2008) Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat. Genet. 40: 1253–60.
[35]  The International HapMap Consortium (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature. 449: 851–61.
[36]  Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 38: 904–9.
[37]  Yamaguchi-Kabata Y, Nakazono K, A AT, Saito S, Hosono N, et al. (2008) Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. Am. J. Hum. Genet. 83: 445–56.
[38]  Quesenberry CP, Hales C (1980) Concentration bands for uniformity plots. J. Statist. Comput. Simul. 11: 41–53.


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