Human Genetics

, Volume 128, Issue 5, pp 491–499

Nicotinic acetylcholine receptor genes on chromosome 15q25.1 are associated with nicotine and opioid dependence severity

  • Porat M. Erlich
  • Stuart N. Hoffman
  • Margaret Rukstalis
  • John J. Han
  • Xin Chu
  • W. H. Linda Kao
  • Glenn S. Gerhard
  • Walter F. Stewart
  • Joseph A. Boscarino
Original Investigation


A locus on chromosome 15q25.1 previously implicated in nicotine, alcohol, and cocaine dependence, smoking, and lung cancer encodes subunits of the nicotinic acetylcholine receptor (nAChR) expressed in the mesolimbic system and thought to mediate substance dependence. Opioid dependence severity (ODS), nicotine dependence severity (NDS), smoking status and quantity, and the number of attempts to quit were assessed using questionnaire instruments in 505 subjects who were prescribed opioid medications for chronic pain in outpatient practice sites. Multivariate regression was used to test for genetic association of these phenotypes with 5 SNPs in the nAChR gene cluster on chromosome 15q25.1, adjusting for background variables. A coding variant in CHRNA5 (rs16969968[A]) was significantly associated with 1.4-unit higher ODS (p < 0.00017). A variant in the 3′ untranslated region of CHRNA3 (rs660652[G]) was significantly associated with 1.7-fold higher odds of lifetime smoking (p < 0.0092), 1.1-unit higher NDS (p < 0.0007), 0.7 more pack-years of cigarette smoking (p < 0.0038), and 0.8 more lifetime attempts to quit (p < 0.0084). Our data suggest an association of DNA variants in the nAChR gene cluster on chromosome 15q25.1 with ODS, as well as NDS and related smoking phenotypes. While the association of this locus with NDS and smoking phenotypes is well known, the association with ODS, a dimension of opioid substance dependence, is novel and requires verification in independent studies.



Linkage disequilibrium


Polymerase chain reaction


Minor allele frequency


Opioid dependence severity


Severity of dependence scale


Nicotine dependence severity


Fagerstrom tolerance scale


Electronic health record


Nicotinic acetylcholine receptor


Cholinergic receptor nicotinic alpha


Single nucleotide polymorphism


  1. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders. American Psychiatric Publishing, ArlingtonGoogle Scholar
  2. Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J et al (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet 40:616–622CrossRefPubMedGoogle Scholar
  3. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265CrossRefPubMedGoogle Scholar
  4. Berrettini W, Yuan X, Tozzi F, Song K, Francks C, Chilcoat H, Waterworth D, Muglia P, Mooser V (2008) Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking. Mol Psychiatry 13:368–373CrossRefPubMedGoogle Scholar
  5. Bierut LJ, Stitzel JA, Wang JC, Hinrichs AL, Grucza RA, Xuei X, Saccone NL, Saccone SF, Bertelsen S, Fox L et al (2008) Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165:1163–1171CrossRefPubMedGoogle Scholar
  6. Boscarino JA, Rukstalis M, Hoffman SN, Han JJ, Erlich PM, Gerhard GS, Stewart WF (2010) Risk factors for drug dependence among outpatients on opioid therapy in a large US healthcare system. Addiction 105 (in press)Google Scholar
  7. Centers for Disease Control and Prevention (2009) Current smoking. CDC/National Center for Health StatisticsGoogle Scholar
  8. Cleeland CS, Ryan KM (1994) Pain assessment: global use of the brief pain inventory. Ann Acad Med Singap 23:129–138PubMedGoogle Scholar
  9. de Bakker PI, Yelensky R, Pe’er I, Gabriel SB, Daly MJ, Altshuler D (2005) Efficiency and power in genetic association studies. Nat Genet 37:1217–1223CrossRefPubMedGoogle Scholar
  10. Fagerstrom KO (1978) Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav 3:235–241CrossRefPubMedGoogle Scholar
  11. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M et al (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229CrossRefPubMedGoogle Scholar
  12. Gossop M, Darke S, Griffiths P, Hando J, Powis B, Hall W, Strang J (1995) The severity of dependence scale (SDS): psychometric properties of the SDS in English and Australian samples of heroin, cocaine and amphetamine users. Addiction 90:607–614CrossRefPubMedGoogle Scholar
  13. Grucza RA, Wang JC, Stitzel JA, Hinrichs AL, Saccone SF, Saccone NL, Bucholz KK, Cloninger CR, Neuman RJ, Budde JP et al (2008) A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biol Psychiatry 64:922–929CrossRefPubMedGoogle Scholar
  14. Hays JT, Ebbert JO (2008) Varenicline for tobacco dependence. N Engl J Med 359:2018–2024CrossRefPubMedGoogle Scholar
  15. Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO (1991) The fagerstrom test for nicotine dependence: a revision of the fagerstrom tolerance questionnaire. Br J Addict 86:1119–1127CrossRefPubMedGoogle Scholar
  16. Heitjan DF, Asch DA, Ray R, Rukstalis M, Patterson F, Lerman C (2008) Cost-effectiveness of pharmacogenetic testing to tailor smoking-cessation treatment. Pharmacogenomics J 8:391–399CrossRefPubMedGoogle Scholar
  17. Hogarth L, Duka T (2006) Human nicotine conditioning requires explicit contingency knowledge: is addictive behaviour cognitively mediated? Psychopharmacology (Berl) 184:553–566CrossRefGoogle Scholar
  18. Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P et al (2008) A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452:633–637CrossRefPubMedGoogle Scholar
  19. Janhunen S, Ahtee L (2007) Differential nicotinic regulation of the nigrostriatal and mesolimbic dopaminergic pathways: implications for drug development. Neurosci Biobehav Rev 31:287–314CrossRefPubMedGoogle Scholar
  20. Johnstone EC, York EE, Walton RT (2002) Genetic testing: the future of smoking cessation therapy? Expert Rev Mol Diagn 2:60–68CrossRefPubMedGoogle Scholar
  21. Joslyn G, Brush G, Robertson M, Smith TL, Kalmijn J, Schuckit M, White RL (2008) Chromosome 15q25.1 genetic markers associated with level of response to alcohol in humans. Proc Natl Acad Sci USA 105:20368–20373CrossRefPubMedGoogle Scholar
  22. Kaye S, Darke S (2002) Determining a diagnostic cut-off on the severity of dependence scale (SDS) for cocaine dependence. Addiction 97:727–731CrossRefPubMedGoogle Scholar
  23. Kessler RC, Ustun TB (2004) The world mental health (WMH) survey initiative version of the world health organization (WHO) composite international diagnostic interview (CIDI). Int J Methods Psychiatr Res 13:93–121CrossRefPubMedGoogle Scholar
  24. Lessov CN, Martin NG, Statham DJ, Todorov AA, Slutske WS, Bucholz KK, Heath AC, Madden PA (2004) Defining nicotine dependence for genetic research: evidence from Australian twins. Psychol Med 34:865–879CrossRefPubMedGoogle Scholar
  25. Li MD (2006) The genetics of nicotine dependence. Curr Psychiatry Rep 8:158–164CrossRefPubMedGoogle Scholar
  26. Li MD, Burmeister M (2009) New insights into the genetics of addiction. Nat Rev Genet 10:225–231CrossRefPubMedGoogle Scholar
  27. Li TK, Volkow ND, Baler RD, Egli M (2007) The biological bases of nicotine and alcohol co-addiction. Biol Psychiatry 61:1–3CrossRefPubMedGoogle Scholar
  28. Lips EH, Gaborieau V, McKay JD, Chabrier A, Hung RJ, Boffetta P, Hashibe M, Zaridze D, Szeszenia-Dabrowska N, Lissowska J et al (2010) Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals. Int J Epidemiol 39:563–577CrossRefPubMedGoogle Scholar
  29. Portugal GS, Gould TJ (2008) Genetic variability in nicotinic acetylcholine receptors and nicotine addiction: converging evidence from human and animal research. Behav Brain Res 193:1–16CrossRefPubMedGoogle Scholar
  30. R Development Core Team (2008) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  31. Robinson TE, Berridge KC (2008) Review. The incentive sensitization theory of addiction: some current issues. Phil Trans R Soc Lond B Biol Sci 363:3137–3146CrossRefGoogle Scholar
  32. Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau O et al (2007) Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 16:36–49CrossRefPubMedGoogle Scholar
  33. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434CrossRefPubMedGoogle Scholar
  34. Sherva R, Kranzler HR, Yu Y, Logue MW, Poling J, Arias AJ, Anton RF, Oslin D, Farrer LA, Gelernter J (2010) Variation in nicotinic acetylcholine receptor genes is associated with multiple substance dependence phenotypes. Neuropsychopharmacology 35(9):1921–1931Google Scholar
  35. Spitz MR, Amos CI, Dong Q, Lin J, Wu X (2008) The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer. J Natl Cancer Inst 100:1552–1556CrossRefPubMedGoogle Scholar
  36. Sullivan PF, Kendler KS (1999) The genetic epidemiology of smoking. Nicotine Tob Res 1(Suppl 2):S51–S57 discussion S69–S70CrossRefPubMedGoogle Scholar
  37. Tan G, Jensen MP, Thornby JI, Shanti BF (2004) Validation of the brief pain inventory for chronic nonmalignant pain. J Pain 5:133–137CrossRefPubMedGoogle Scholar
  38. The Clinical Practice Guideline Treating Tobacco Use and Dependence 2008 Update Panel, Liaisons, and Staff (2008) A clinical practice guideline for treating tobacco use and dependence: 2008 update. A U.S. public health service report. Am J Prev Med 35:158–176Google Scholar
  39. Thorgeirsson TE, Geller F, Sulem P, Rafnar T, Wiste A, Magnusson KP, Manolescu A, Thorleifsson G, Stefansson H, Ingason A et al (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452:638–642CrossRefPubMedGoogle Scholar
  40. Wang Y, Broderick P, Webb E, Wu X, Vijayakrishnan J, Matakidou A, Qureshi M, Dong Q, Gu X, Chen WV et al (2008) Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet 40:1407–1409CrossRefPubMedGoogle Scholar
  41. Wang JC, Grucza R, Cruchaga C, Hinrichs AL, Bertelsen S, Budde JP, Fox L, Goldstein E, Reyes O, Saccone N et al (2009) Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Mol Psychiatry 14:501–510CrossRefPubMedGoogle Scholar
  42. World Health Organization (2009) The severity of dependence scale (SDS). World Health OrganizationGoogle Scholar
  43. Wu LT, Woody GE, Yang C, Pan JJ, Blazer DG (2010) Abuse and dependence on prescription opioids in adults: a mixture categorical and dimensional approach to diagnostic classification. Psychol Med 12:1–13 [Epub ahead of print]Google Scholar
  44. Xian H, Scherrer JF, Grant JD, Eisen SA, True WR, Jacob T, Bucholz KK (2008) Genetic and environmental contributions to nicotine, alcohol and cannabis dependence in male twins. Addiction 103:1391–1398CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Porat M. Erlich
    • 1
    • 2
  • Stuart N. Hoffman
    • 3
  • Margaret Rukstalis
    • 1
  • John J. Han
    • 4
  • Xin Chu
    • 5
  • W. H. Linda Kao
    • 6
  • Glenn S. Gerhard
    • 5
  • Walter F. Stewart
    • 1
    • 6
  • Joseph A. Boscarino
    • 1
    • 7
    • 8
  1. 1.Center for Health ResearchGeisinger Health SystemDanvilleUSA
  2. 2.Department of MedicineTemple School of MedicinePhiladelphiaUSA
  3. 3.Department of NeurologyGeisinger Health SystemDanvilleUSA
  4. 4.Department of Pain MedicineGeisinger Health SystemDanvilleUSA
  5. 5.Weis CenterGeisinger Health SystemDanvilleUSA
  6. 6.Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  7. 7.Department of Medicine and PediatricsMt Sinai School of MedicineNew YorkUSA
  8. 8.Department of PsychiatryTemple School of MedicinePhiladelphiaUSA

Personalised recommendations