title: NCAM1-TTC12-ANKK1-DRD2 variants and smoking motives as intermediate phenotypes for nicotine dependence.
abstract: BACKGROUND
  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.
authors.affiliation: Center for Alcohol and Addition Studies, Department of Behavioral and Social Sciences, Brown University, Box G-S121-4, Providence, RI, 02912, USA, Cinnamon_Bidwell@brown.edu.
authors.forename: L C
authors.initials: LC
authors.lastname: Bidwell
authors.forename: J E
authors.initials: JE
authors.lastname: McGeary
authors.forename: J C
authors.initials: JC
authors.lastname: Gray
authors.forename: R H C
authors.initials: RH
authors.lastname: Palmer
authors.forename: V S
authors.initials: VS
authors.lastname: Knopik
authors.forename: J
authors.initials: J
authors.lastname: MacKillop
mesh_terms: D000293:Adolescent; D000328:Adult; D019002:CD56 Antigen / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D009042:Motivation / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012907:Smoking / Q000453:epidemiology / Q000235:genetics; D014029:Tobacco Use Disorder / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D019002:CD56 Antigen; C581293:DRD2 protein, human; C522918:NCAM1 protein, human; D011506:Proteins; D017448:Receptors, Dopamine D2; C487552:TTC12 protein, human; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases