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Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background

The Pharmacogenomics Journal volume 8, pages 209–219 (2008)Cite this article

Abstract

The significant worldwide health burden introduced by tobacco smoking highlights the importance of studying the genetic determinants of smoking behavior and the key factor sustaining compulsive smoking, that is, nicotine dependence (ND). We have here addressed the genetic background of smoking in a special study sample of twins, harmonized for early life events and specifically ascertained for smoking from the nationwide twin cohort of the genetically unique population of Finland. The twins and their families were carefully examined for extensive phenotype profiles and a genome-wide scan was performed to identify loci behind the smoking status, ND and the comorbid phenotype of ND and alcohol use in 505 individuals from 153 families. We replicated previous linkage findings on 10q (max logarithm of the odds (LOD) 3.12) for a smoker phenotype, and on 7q and 11p (max LOD 2.50, and 2.25, respectively) for the ND phenotype. The loci linked for ND also showed evidence for linkage for the comorbid phenotype. Our study provides confirmatory evidence for the involvement of these genome regions in the genetic etiology of smoking behavior and ND and for the first time associates drinking and smoking to a shared locus on 10q.

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Abbreviations

ASP:

affected sibpair

DSM-IV:

Diagnostic and Statistical Manual of Mental Disorders, 4th edition

DZ:

dizygotic

FTND:

Fagerström Test for Nicotine Dependence

HSI:

Heaviness of Smoking Index

MZ:

monozygotic

ND:

nicotine dependence

UCSC:

University of California Santa Cruz

References

  1. Doll R, Peto R, Boreham J, Sutherland I . Mortality in relation to smoking: 50 years' observations on male British doctors. BMJ 2004; 328: 1519–1528.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Shafey O, Dolwick S, Guindon GE (eds). Tobacco Control Country Profiles. American Cancer Society: Atlanta, GA, 2003.

    Google Scholar 

  3. True WR, Xian H, Scherrer JF, Madden PAF, Bucholz KK, Heath AC et al. Common genetic vulnerability for nicotine and alcohol dependence in men. Arch Gen Psychiatry 1999; 56: 655–661.

    Article  CAS  PubMed  Google Scholar 

  4. Kendler KS, Neale MC, Sullivan P, Corey LA, Gardner CO, Prescott CA . A population-based twin study in women of smoking initiation and nicotine dependence. Psychol Med 1999; 29: 299–308.

    Article  CAS  PubMed  Google Scholar 

  5. Lessov CN, Martin NG, Statham DJ, Todorov AA, Slutske WS, Bucholz KK et al. Defining nicotine dependence for genetic research: evidence from Australian twins. Psychol Med 2004; 34: 865–879.

    Article  PubMed  Google Scholar 

  6. Maes HH, Sullivan PF, Bulik CM, Neale MC, Prescott CA, Eaves LJ 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.

    Article  PubMed  Google Scholar 

  7. Vink JM, Beem AL, Posthuma D, Neale MC, Willemsen G, Kendler KS et al. Linkage analysis of smoking initiation and quantity in Dutch sibling pairs. Pharmacogenomics J 2004; 4: 274–282, Erratum in: Pharmacogenomics J 2004; 4: 345–346.

    Article  CAS  PubMed  Google Scholar 

  8. Hämäläinen J, Kaprio J, Isometsä E, Heikkinen M, Poikolainen, Lindeman S et al. Cigarette smoking, alcohol intoxication and major depressive episode in a representative population sample. J Epidemiol Community Health 2001; 55: 573–576.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Johnson EO, Rhee SH, Chase GA, Breslau N . Comorbidity of depression with levels of smoking: an exploration of the shared familial risk hypothesis. Nicotine Tob Res 2004; 6: 1029–1038.

    Article  PubMed  Google Scholar 

  10. Straub RE, Sullivan PF, Ma Y, Myakishev MV, Harris-Kerr C, Wormley B et al. Susceptibility genes for nicotine dependence: a genome scan and follow-up in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study. Mol Psychiatry 1999; 4: 129–144.

    Article  CAS  PubMed  Google Scholar 

  11. Sullivan PF, Neale BM, van den Oord E, Miles MF, Neale MC, Bulik CM et al. Candidate genes for nicotine dependence via linkage, epistasis, and bioinformatics. Am J Med Genet B Neuropsychiatr Genet 2004; 126: 23–36.

    Article  Google Scholar 

  12. Swan GE, Hops H, Wilhelmsen KC, Lessov-Schlaggar CN, Cheng LS-C, Hudmon KS et al. A genome-wide screen for nicotine dependence susceptibility loci. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 358–360.

    Article  Google Scholar 

  13. Li MD, Payne TJ, Ma JZ, Lou XY, Zhang D, Dupont RT 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.

    Article  CAS  PubMed  Google Scholar 

  14. Duggirala R, Almasy L, Blangero J . Smoking behavior is under the influence of a major quantitative trait locus on human chromosome 5q. Genet Epidemiol 1999; 17: S139–S144.

    Article  PubMed  Google Scholar 

  15. Li MD, Ma JZ, Cheng R, Dupont RD, Williams NJ, Crews KM et al. A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population. BMC Genet 2003; 4: S103–S107.

    Article  PubMed  Google Scholar 

  16. Morley KI, Medland SE, Ferreira MA, Lynskey MT, Montgomery GW, Heath AC et al. A possible smoking susceptibility locus on chromosome 11p12: evidence from sex-limitation linkage analyses in a sample of Australian twin families. Behav Genet 2006; 36: 87–99.

    Article  PubMed  Google Scholar 

  17. Gelernter J, Liu X, Hesselbrock V, Page GP, Goddard A, Zhang H . 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; 128: 94–101.

    Article  Google Scholar 

  18. Bierut LJ, Rice JP, Goate A, Hinrichs AL, Saccone NL, Foroud T 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.

    Article  Google Scholar 

  19. Kaprio J, Koskenvuo M, Sarna S . Cigarette smoking, use of alcohol, and leisure-time physical activity among same-sexed adult male twins. Prog Clin Biol Res 1981; 69: 37–46.

    PubMed  Google Scholar 

  20. Istvan J, Matarazzo JD . Tobacco, alcohol, and caffeine use: a review of their interrelationships. Psychol Bull 1984; 95: 301–326.

    Article  CAS  PubMed  Google Scholar 

  21. Maletzky BM, Klotter J . Smoking and alcoholism. Am J Psychiatry 1974; 131: 445–447.

    CAS  PubMed  Google Scholar 

  22. Kaprio J, Hammar N, Koskenvuo M, Floderus-Myrhed B, Langinvainio H, Sarna S . Cigarette smoking and alcohol use in Finland and Sweden: a cross-national twin study. Int J Epidemiol 1982; 11: 378–386.

    Article  CAS  PubMed  Google Scholar 

  23. Battjes RJ . Smoking as an issue in alcohol and drug abuse treatment. Addict Behav 1988; 13: 225–230.

    Article  CAS  PubMed  Google Scholar 

  24. Swan GE, Carmelli D, Cardon LR . Heavy consumption of cigarettes, alcohol and coffee in male twins. J Stud Alcohol 1997; 58: 182–190.

    Article  CAS  PubMed  Google Scholar 

  25. Madden PA, Bucholz KK, Martin NG, Heath AC . Smoking and the genetic contribution to alcohol-dependence risk. Alcohol Res Health 2000; 24: 209–214.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Batel P, Pessione F, Maitre C, Rueff B . Relationship between alcohol and tobacco dependencies among alcoholics who smoke. Addiction 1995; 90: 977–980.

    Article  CAS  PubMed  Google Scholar 

  27. Helakorpi S, Patja K, Prättälä R, Uutela A . Suomalaisen aikuisväestön terveyskäyttäytyminen ja terveys, kevät 2005. Health Behavior and Health among the Finnish Adult Population, Spring 2005. Kansanterveyslaitoksen julkaisuja B 18/2005 Publications of the National Public Health Institute B 18/2005: Helsinki, 2005.

    Google Scholar 

  28. Warner KE, Burns DM . Hardening and the hard-core smoker: concepts, evidence, and implications. Nicotine Tob Res 2003; 5: 37–48.

    Article  PubMed  Google Scholar 

  29. Goode EL, Badzioch MD, Kim H, Gagnon F, Rozek LS, Edwards KL et al. Framingham Heart Study Multiple genome-wide analyses of smoking behavior in the Framingham Heart Study. BMC Genet 2003; 4: S102.

    Article  PubMed  Google Scholar 

  30. Bergen AW, Yang XR, Bai Y, Beerman MB, Goldstein AM, Goldin LR, Framingham Heart Study. Genomic regions linked to alcohol consumption in the Framingham Heart Study. BMC Genet 2003; 4 (Suppl 1): S101.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bergen AW, Korczak JF, Weissbecker KA, Goldstein AM . A genome-wide search for loci contributing to smoking and alcoholism. Genet Epidemiol 1999; 17: S55–S60.

    Article  PubMed  Google Scholar 

  32. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press: Washington, DC, 1994.

  33. Heatherton TF, Kozlowski LT, Frecker RC, Fagerström K-O . The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict 1991; 86: 1119–1127.

    Article  CAS  PubMed  Google Scholar 

  34. Heatherton TF, Kozlowski LT, Frecker RC, Rickert W, Robinson J . Measuring the heaviness of smoking: using self-reported time to the first cigarette of the day and number of cigarettes smoked per day. Br J Addict 1989; 84: 791–799.

    Article  CAS  PubMed  Google Scholar 

  35. Peltonen L, Palotie A, Lange K . Use of population isolates for mapping complex traits. Nat Rev Genet 2000; 1: 182–190.

    Article  CAS  PubMed  Google Scholar 

  36. Broms U, Silventoinen K, Madden PAF, Heath AC, Kaprio J . Genetic architecture of smoking behaviour: a study of Finnish adult twins. Twin Res Hum Genet 2006; 9: 64–72.

    Article  PubMed  Google Scholar 

  37. Armstrong BK, White E, Saracci R . Principles of exposure measurement in Epidemiology. Monographs in Epidemiology and Biostatistics, vol. 21. Oxford University Press: New York, 1994.

    Google Scholar 

  38. Vartiainen E, Seppälä T, Lillsunde P, Puska P . Validation of self reported smoking by serum cotinine measurement in a community-based study. J Epidemiol Community Health 2002; 56: 167–170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Madden PA, Heath AC, Pedersen NL, Kaprio J, Koskenvuo MJ, Martin NG . The genetics of smoking persistence in men and women: a multicultural study. Behav Genet 1999; 29: 423–431.

    Article  CAS  PubMed  Google Scholar 

  40. Madden PA, Pedersen NL, Kaprio J, Koskenvuo MJ, Martin NG . The epidemiology and genetics of smoking initiation and persistence: crosscultural comparisons of twin study results. Twin Res 2004; 7: 82–97.

    Article  PubMed  Google Scholar 

  41. Fagerström KO . Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav 1978; 3: 235–241.

    Article  PubMed  Google Scholar 

  42. Fagerström KO, Schneider NG . Measuring nicotine dependence: a review of the Fagerström Tolerance Questionnaire. J Behav Med 1989; 12: 159–182.

    Article  PubMed  Google Scholar 

  43. CDC. Annual smoking-attributable mortality, years of potential life lost, and productivity losses – United States, 1997–2001. MMWR 2005; 54: 625–628.

    Article  Google Scholar 

  44. Haukkala A, Laaksonen M, Uutela A . Smokers who do not want to quit – is consonant smoking related to lifestyle and socioeconomic factors? Scand J Public Health 2001; 29: 226–232.

    Article  CAS  PubMed  Google Scholar 

  45. Helakorpi S, Berg M, Uutela A, Puska P . Suomalaisen aikuisväestön terveyskäyttäytyminen, kevät 1994. Health behaviour among Finnish adult population, Spring 1994. Kansanterveyslaitoksen julkaisuja B 8/1994 Publications of the National Public Health Institute B 8/1994: Helsinki, 1994.

  46. Moolchan ET, Radzius A, Epstein DH, Uhl G, Gorelick DA, Cadet JL et al. The Fagerström Test for Nicotine Dependence and the Diagnostic Interview Schedule. Addict Behav 2002; 27: 101–113.

    Article  PubMed  Google Scholar 

  47. Etter JF . A comparison of the content-, construct- and predictive validity of the cigarette dependence scale and the Fagerström test for nicotine dependence. Drug Alcohol Depend 2005; 77: 259–268.

    Article  PubMed  Google Scholar 

  48. Ekelund J, Lichtermann D, Hovatta I, Ellonen P, Suvisaari J, Terwilliger JD et al. Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. Hum Mol Genet 2000; 9: 1049–1057.

    Article  CAS  PubMed  Google Scholar 

  49. Madden PA, Heath AC . Shared genetic vulnerability in alcohol and cigarette use and dependence. Alcohol Clin Exp Res 2002; 26: 1919–1921.

    Article  PubMed  Google Scholar 

  50. Ye Y, Zhong X, Zhang H . A genome-wide tree- and forest-based association analysis of comorbidity of alcoholism and smoking. BMC Genet 2005; 6: S135.

    Article  PubMed  Google Scholar 

  51. Kaprio J, Koskenvuo M . Genetic and environmental factors in complex diseases: the Older Finnish Twin Cohort. Twin Res 2002; 5: 358–365.

    Article  PubMed  Google Scholar 

  52. Bucholz KK, Cadoret R, Cloninger CR, Dinwiddie SH, Hesselbrock VM, Nurnberger Jr JI et al. A new, semi-structured psychiatric interview for use in genetic linkage studies: a report on the reliability of the SSAGA. J Stud Alcohol 1994; 55: 149–158.

    Article  CAS  PubMed  Google Scholar 

  53. Cottler LB, Robins LN, Grant BF, Blaine J, Towle LH, Wittchen HU et al. The CIDI-core substance abuse and dependence questions: cross-cultural and nosological issues. The WHO/ADAMHA field trial. Br J Psychiatry 1991; 159: 653–658.

    Article  CAS  PubMed  Google Scholar 

  54. Kauhanen J, Kaplan GA, Goldberg DE, Salonen JT . Beer binging and mortality: results from the Kuopio ischaemic heart disease risk factor study, a prospective population based study. BMJ 1997; 315: 846–851.

    Article  CAS  PubMed  Google Scholar 

  55. Järvenpää T, Rinne JO, Koskenvuo M, Räihä I, Kaprio J . Binge drinking in midlife and dementia risk. Epidemiology 2005; 16: 766–771.

    Article  PubMed  Google Scholar 

  56. O'Connell JR, Weeks DE . PedCheck: a program for identifying genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . GRR: graphical representation of relationship errors. Bioinformatics 2001; 17: 742–743.

    Article  CAS  PubMed  Google Scholar 

  58. Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B et al. A high-resolution recombination map of the human genome. Nat Genet 2002; 31: 241–247.

    Article  CAS  PubMed  Google Scholar 

  59. Lichter JB, Barr CL, Kennedy JL, Van Tol HH, Kidd KK, Livak KJ . A hypervariable segment in the human dopamine receptor D4 (DRD4) gene. Hum Mol Genet 1993; 2: 767–773.

    Article  CAS  PubMed  Google Scholar 

  60. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.

    Article  CAS  PubMed  Google Scholar 

  61. Hiekkalinna T, Terwilliger JD, Sammalisto S, Peltonen L, Perola M . AUTOGSCAN: powerful tools for automated genome-wide linkage and linkage disequilibrium analysis. Twin Res Hum Genet 2005; 8: 16–21.

    Article  PubMed  Google Scholar 

  62. Göring HHH, Terwilliger JD . Linkage analysis in the presence of errors IV: joint pseudomarker analysis of linkage and/or linkage disequilibrium on a mixture of pedigrees and singletons when the mode of inheritance cannot be accurately specified. Am J Hum Genet 2000; 66: 1310–1327.

    Article  PubMed  Google Scholar 

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Acknowledgements

We are grateful to the participating families for their patience and contribution. We express our appreciation to the skillful study interviewers: A Häppölä, A-M Iivonen, K Karhu, H-M Kuha, U Kulmala-Gråhn, M Mantere, K Saanakorpi, M Saarinen, R Sipilä, L Viljanen and E Voipio. We are grateful to D Statham for helping to train the interviewers. We thank P Ruokolinna for thorough data entering. We thank the excellent staff at the Finnish Genome Center: S Ekström, A Yliperttula, A Korvenpää and M Baarman for producing the genotype data, A Sarahonka and V Leppä for diligently reviewing the genotype data, A Leinonen and J Hinkula for careful data cleaning procedures and Dr J Muilu for supervising the data management team. The study is funded by the Academy of Finland Post-doctoral Fellowship to A Loukola, by Doctoral Programs of Public Health, University of Helsinki, Finland to support U Broms, by GenomEUtwin (European Union Contract No. QLG2-CT-2002-01254) to J Kaprio and L Peltonen, by NIH grant DA12854 to PAF Madden, and by Center of Excellence in Disease Genetics, Academy of Finland to L Peltonen. Data collection was supported by a NIH grant DA12854 to PAF Madden and by Academy of Finland grants to J Kaprio and M Koskenvuo. ML Pergadia is supported by NIH grant DA019951. This study forms a part of the research program of the Academy of Finland Center of Excellence in Complex Disease Genetics.

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Authors and Affiliations

  1. Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland

    A Loukola, H Maunu, A Salo, E Nyman, S Sammalisto, M Perola & L Peltonen

  2. Finnish Genome Center, University of Helsinki, Helsinki, Finland

    A Loukola & E Widén

  3. Department of Public Health, University of Helsinki, Helsinki, Finland

    U Broms, H Maunu, K Heikkilä, M Siivola, A Salo & J Kaprio

  4. Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland

    U Broms & J Kaprio

  5. Department of Psychiatry and Midwest Alcoholism Research Center, Washington University School of Medicine, St Louis, MO, USA

    M L Pergadia, A Agrawal, A C Heath & P A F Madden

  6. Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    N G Martin

  7. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    L Peltonen

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  1. A Loukola
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  2. U Broms
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  3. H Maunu
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  10. S Sammalisto
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Correspondence to J Kaprio.

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Loukola, A., Broms, U., Maunu, H. et al. Linkage of nicotine dependence and smoking behavior on 10q, 7q and 11p in twins with homogeneous genetic background. Pharmacogenomics J 8, 209–219 (2008). https://doi.org/10.1038/sj.tpj.6500464

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