, 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



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.


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


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.


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.


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.


Haplotype SNP Dopamine Nicotine Endophenotype 


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.


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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

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