Advertisement

Psychopharmacology

, Volume 232, Issue 7, pp 1177–1186 | Cite as

NCAM1-TTC12-ANKK1-DRD2 variants and smoking motives as intermediate phenotypes for nicotine dependence

  • L. C. Bidwell
  • J. E. McGeary
  • J. C. Gray
  • R. H. C. Palmer
  • V. S. Knopik
  • J. MacKillop
Original Investigation

Abstract

Rationale

Nicotine dependence (ND) is a heterogeneous phenotype with complex genetic influences. The use of intermediate ND phenotypes may clarify genetic influences and reveal specific etiological pathways. Prior work has found that the four Primary Dependence Motives (PDM) subscales (Automaticity, Craving, Loss of Control, and Tolerance) of the Wisconsin Inventory of Smoking Motives (WISDM) represent heavy, pervasive smoking, which is a core feature of nicotine dependence, making these motives strong candidates as intermediate phenotypes.

Objective

This study examines the WISDM PDM as a novel intermediate phenotype of nicotine dependence.

Methods

The study used data from 734 European Americans who smoked at least 5 cigs/day [M = 16.2 (SD = 9.5) cigs/day], completed a phenotypic assessment, and provided a sample of DNA. Based on prior evidence of the role of genetic variation in the NCAM1-TTC12-ANKK1-DRD2 region on chromosome 11q23 in smoking behavior, associations among 12 region loci with nicotine dependence and PDM phenotypes were examined using haplotype and individual loci approaches. In addition, mediational analysis tested the indirect pathway from genetic variation to smoking motives to nicotine dependence.

Results

NCAM1-TTC12-ANKK1-DRD2 region loci and haplotypes were significantly associated with the motive of Automaticity and, further, Automaticity significantly mediated associations among NCAM1-TTC12-ANKK1-DRD2 cluster variants and nicotine dependence.

Conclusions

These results suggest that motives related to automaticity are a viable intermediate phenotype for understanding genetic contributions to nicotine dependence. Further, NCAM1-TTC12-ANKK1-DRD2 variants may increase the likelihood that a person will become dependent via a highly automatic smoking ritual that can be elicited with little awareness.

Keywords

Haplotype SNP Dopamine Nicotine Endophenotype 

Notes

Conflict of interest

Funding was provided by the following grants: SAPRP 65626 from the Robert Wood Johnson Foundation and K23 AA016936 from NIH to James MacKillop; K23 DA033302 from NIDA to L. Cinnamon Bidwell; a Research Career Development Award from the Medical Research Service of the Department of Veteran Affairs, 1S10RR023457-01A1 and Shared equipment grants (ShEEP) from the Medical Research Service of the Department of Veteran Affairs to John McGeary; K01 AA021113 from NIAAA to Rohan Palmer; and R01 DA023134 from NIDA to Valerie Knopik. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. Dr. MacKillop is the holder of the Boris Chair in Addictions Research, which partially supported his contributions. The authors have no conflicts of interest to report.

References

  1. (NCI) NCI (2009) Phenotypes and endophenotypes: foundations for genetic studies of nicotine use and dependence. National Cancer Institute Tobacco Control Monograph Series No. 20, Bethesda, p 654Google Scholar
  2. Baker TB, Weiss RB, Bolt D, von Niederhausern A, Fiore MC, Dunn DM, Piper ME, Matsunami N, Smith SS, Coon H, McMahon WM, Scholand MB, Singh N, Hoidal JR, Kim SY, Leppert MF, Cannon DS (2009) Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes. Nicotine Tob Res 11:785–796CrossRefPubMedCentralPubMedGoogle Scholar
  3. Barrett JC (2009) Haploview: Visualization and analysis of SNP genotype data. Cold Spring Harb Protoc 2009: pdb ip71Google Scholar
  4. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265CrossRefPubMedGoogle Scholar
  5. Benjamini Y, Hochberg Y (1995) Multiple testing. J R Stat Soc Ser B Methodol 57:289–300Google Scholar
  6. Benowitz NL (2010) Nicotine addiction. N Engl J Med 362:2295–2303CrossRefPubMedCentralPubMedGoogle Scholar
  7. Bergen AW, Conti DV, Van Den Berg D, Lee W, Liu J, Li D, Guo N, Mi H, Thomas PD, Lessov-Schlaggar CN, Krasnow R, He Y, Nishita D, Jiang R, McClure JB, Tildesley E, Hops H, Tyndale RF, Benowitz NL, Lerman C, Swan GE (2009) Dopamine genes and nicotine dependence in treatment-seeking and community smokers. Neuropsychopharmacology 34:2252–2264CrossRefPubMedCentralPubMedGoogle Scholar
  8. Ducci F, Kaakinen M, Pouta A, Hartikainen AL, Veijola J, Isohanni M, Charoen P, Coin L, Hoggart C, Ekelund J, Peltonen L, Freimer N, Elliott P, Schumann G, Jarvelin MR (2011) TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4 influence different pathways leading to smoking behavior from adolescence to mid-adulthood. Biol Psychiatry 69:650–660CrossRefPubMedCentralPubMedGoogle Scholar
  9. Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8:1481–1489CrossRefPubMedGoogle Scholar
  10. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229CrossRefPubMedGoogle Scholar
  11. Gauderman WJ (2002) Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol 155:478–484CrossRefPubMedGoogle Scholar
  12. Gelernter J, Yu Y, Weiss R, Brady K, Panhuysen C, Yang BZ, Kranzler HR, Farrer L (2006) Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations. Hum Mol Genet 15:3498–3507CrossRefPubMedGoogle Scholar
  13. Gelernter J, Panhuysen C, Weiss R, Brady K, Poling J, Krauthammer M, Farrer L, Kranzler HR (2007) Genomewide linkage scan for nicotine dependence: identification of a chromosome 5 risk locus. Biol Psychiatry 61:119–126CrossRefPubMedGoogle Scholar
  14. Goldman D, Ducci F (2007) Deconstruction of vulnerability to complex diseases: enhanced effect sizes and power of intermediate phenotypes. ScientificWorldJournal 7:124–130CrossRefPubMedGoogle Scholar
  15. Goldman D, Oroszi G, Ducci F (2005) The genetics of addictions: uncovering the genes. Nat Rev Genet 6:521–532CrossRefPubMedGoogle Scholar
  16. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160:636–645CrossRefPubMedGoogle Scholar
  17. 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
  18. IBM (2010) IBM SPSS statistics for windows, version 19.0. IBM Corp, ArmonkGoogle Scholar
  19. Jonsson EG, Nothen MM, Grunhage F, Farde L, Nakashima Y, Propping P, Sedvall GC (1999) Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry 4:290–296CrossRefPubMedGoogle Scholar
  20. Laucht M, Becker K, Frank J, Schmidt MH, Esser G, Treutlein J, Skowronek MH, Schumann G (2008) Genetic variation in dopamine pathways differentially associated with smoking progression in adolescence. J Am Acad Child Adolesc Psychiatry 47:673–681CrossRefPubMedGoogle Scholar
  21. Li MD, Ma JZ, Beuten J (2004) Progress in searching for susceptibility loci and genes for smoking-related behaviour. Clin Genet 66:382–392CrossRefPubMedGoogle Scholar
  22. Lu J, Wei Q, Bondy ML, Li D, Brewster A, Shete S, Yu TK, Sahin A, Meric-Bernstam F, Hunt KK, Singletary SE, Ross MI, Wang LE (2006) Polymorphisms and haplotypes of the NBS1 gene are associated with risk of sporadic breast cancer in non-Hispanic white women < or = 55 years. Carcinogenesis 27:2209–2216CrossRefPubMedGoogle Scholar
  23. MacKillop J, Munafò M (2013) Genetic influences on addiction: an intermediate phenotype approach. MIT Press, CambridgeGoogle Scholar
  24. MacKillop J, Obasi E, Amlung MT, McGeary JE, Knopik VS (2010) The role of genetics in nicotine dependence: mapping the pathways from genome to syndrome. Curr Cardiovasc Risk Rep 4:446–453CrossRefPubMedCentralPubMedGoogle Scholar
  25. MacKillop J, Few LR, Murphy JG, Wier LM, Acker J, Murphy C, Stojek M, Carrigan M, Chaloupka F (2012) High-resolution behavioral economic analysis of cigarette demand to inform tax policy. Addiction 107:2191–2200CrossRefPubMedCentralPubMedGoogle Scholar
  26. Mackinnon DP, Fairchild AJ (2009) Current directions in mediation analysis. Curr Dir Psychol Sci 18:16CrossRefPubMedCentralPubMedGoogle Scholar
  27. Morley KI, Medland SE, Ferreira MA, Lynskey MT, Montgomery GW, Heath AC, Madden PA, Martin NG (2006) A possible smoking susceptibility locus on chromosome 11p12: evidence from sex-limitation linkage analyses in a sample of Australian twin families. Behavior Genet 36:87–99CrossRefGoogle Scholar
  28. Mota NR, Araujo-Jnr EV, Paixao-Cortes VR, Bortolini MC, Bau CH (2012) Linking dopamine neurotransmission and neurogenesis: the evolutionary history of the NTAD (NCAM1-TTC12-ANKK1-DRD2) gene cluster. Genet Mol Biol 35:912–918CrossRefPubMedCentralPubMedGoogle Scholar
  29. Munafò M, Clark T, Johnstone E, Murphy M, Walton R (2004) The genetic basis for smoking behavior: a systematic review and meta-analysis. Nicotine Tob Res 6:583–597CrossRefPubMedGoogle Scholar
  30. Neville MJ, Johnstone EC, Walton RT (2004) Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat 23:540–545CrossRefPubMedGoogle Scholar
  31. Oroszi G, Anton RF, O’Malley S, Swift R, Pettinati H, Couper D, Yuan Q, Goldman D (2009) OPRM1 Asn40Asp predicts response to naltrexone treatment: a haplotype-based approach. Alcohol Clin Exp Res 33:383–393CrossRefPubMedCentralPubMedGoogle Scholar
  32. Pajewski NM, Parker SD, Poland GA, Ovsyannikova IG, Song W, Zhang K, McKinney BA, Pankratz VS, Edberg JC, Kimberly RP, Jacobson RM, Tang J, Kaslow RA (2011) The role of HLA-DR-DQ haplotypes in variable antibody responses to anthrax vaccine adsorbed. Genes Immun 12:457–465CrossRefPubMedCentralPubMedGoogle Scholar
  33. Pergadia ML, Heath AC, Martin NG, Madden PA (2006) Genetic analyses of DSM-IV nicotine withdrawal in adult twins. Psychol Med 36:963–972CrossRefPubMedGoogle Scholar
  34. Piasecki TM, Piper ME, Baker TB (2010) Refining the tobacco dependence phenotype using the Wisconsin inventory of smoking dependence motives: II. Evidence from a laboratory self-administration assay. J Abnorm Psychol 119:513–523CrossRefPubMedCentralPubMedGoogle Scholar
  35. Piper ME, Piasecki TM, Federman EB, Bolt DM, Smith SS, Fiore MC, Baker TB (2004) A multiple motives approach to tobacco dependence: the Wisconsin inventory of smoking dependence motives (WISDM-68). J Consult Clin Psychol 72:139–154CrossRefPubMedGoogle Scholar
  36. Piper ME, Bolt DM, Kim SY, Japuntich SJ, Smith SS, Niederdeppe J, Cannon DS, Baker TB (2008) Refining the tobacco dependence phenotype using the Wisconsin inventory of smoking dependence motives. J Abnorm Psychol 117:747–761CrossRefPubMedCentralPubMedGoogle Scholar
  37. Pohjalainen T, Rinne JO, Nagren K, Lehikoinen P, Anttila K, Syvalahti EK, Hietala J (1998) The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry 3:256–260CrossRefPubMedGoogle Scholar
  38. Preacher KJ, Hayes AF (2008) Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav Res Methods 40:879–891CrossRefPubMedGoogle Scholar
  39. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575CrossRefPubMedCentralPubMedGoogle Scholar
  40. Robinson JD, Lam CY, Minnix JA, Wetter DW, Tomlinson GE, Minna JD, Chen TT, Cinciripini PM (2007) The DRD2 TaqI-B polymorphism and its relationship to smoking abstinence and withdrawal symptoms. Pharmacogen J 7:266–274CrossRefGoogle Scholar
  41. Saccone SF, Hinrichs AL, Saccone NL, Chase GA, Konvicka K, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau O, Swan GE, Goate AM, Rutter J, Bertelsen S, Fox L, Fugman D, Martin NG, Montgomery GW, Wang JC, Ballinger DG, Rice JP, Bierut LJ (2007) Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs. Hum Mol Genet 16:36–49CrossRefPubMedCentralPubMedGoogle Scholar
  42. Stephens M, Donnelly P (2003) A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162–1169CrossRefPubMedCentralPubMedGoogle Scholar
  43. Stephens M, Scheet P (2005) Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet 76:449–462CrossRefPubMedCentralPubMedGoogle Scholar
  44. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989CrossRefPubMedCentralPubMedGoogle Scholar
  45. Tabachnick BG, Fidell LS (2001) Using multivariate statistics, 4th edn. Allyn &Bacon, BostonGoogle Scholar
  46. Usiello A, Baik JH, Rouge-Pont F, Picetti R, Dierich A, LeMeur M, Piazza PV, Borrelli E (2000) Distinct functions of the two isoforms of dopamine D2 receptors. Nature 408:199–203CrossRefPubMedGoogle Scholar
  47. Volkow ND, Fowler JS, Wang GJ, Baler R, Telang F (2009) Imaging dopamine’s role in drug abuse and addiction. Neuropharmacology 56(1):3–8CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • L. C. Bidwell
    • 1
    • 2
    • 3
  • J. E. McGeary
    • 4
    • 2
    • 3
    • 1
  • J. C. Gray
    • 5
  • R. H. C. Palmer
    • 2
    • 3
  • V. S. Knopik
    • 2
    • 3
  • J. MacKillop
    • 6
  1. 1.Center for Alcohol and Addition Studies, Department of Behavioral and Social SciencesBrown UniversityProvidenceUSA
  2. 2.Division of Behavioral GeneticsRhode Island HospitalProvidenceUSA
  3. 3.Department of Psychiatry and Human Behavior, Alpert Medical SchoolBrown UniversityProvidenceUSA
  4. 4.Providence Veterans Affairs Medical CenterProvidenceUSA
  5. 5.Department of PsychologyUniversity of GeorgiaAthensUSA
  6. 6.Boris Centre for Addictions Research, Department of Psychiatry and Behavioural NeurosciencesMcMaster UniversityHamiltonCanada

Personalised recommendations