title: Genetic variants and early cigarette smoking and nicotine dependence phenotypes in adolescents.
abstract: BACKGROUND
  While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.
  
  
  METHODS
  In a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator).
  
  
  RESULTS
  The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076.
  
  
  CONCLUSIONS
  Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3).
  
  
  CONCLUSIONS
  Dopaminergic pathways may be salient during early smoking and the development of ND.
authors.affiliation: Centre de recherche CHUM, Montreal, Quebec, Canada; Department of Social and Preventive Medicine, University of Montreal, Montreal, Quebec, Canada; Institut national de santé publique du Québec, Montreal, Quebec, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: O'Loughlin
authors.affiliation: Centre de recherche CHUM, Montreal, Quebec, Canada; Department of Social and Preventive Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Sylvestre
authors.affiliation: Department of Epidemiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Labbe
authors.affiliation: Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Low
authors.affiliation: Department of Epidemiology and Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Roy-Gagnon
authors.affiliation: Centre de recherche CHUM, Montreal, Quebec, Canada.
authors.forename: Erika N
authors.initials: EN
authors.lastname: Dugas
authors.affiliation: Centre de recherche CHUM, Montreal, Quebec, Canada; Department of Social and Preventive Medicine, University of Montreal, Montreal, Quebec, Canada; Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Karp
authors.affiliation: Departments of Medicine and Human Genetics, McGill University, Montreal, Quebec, Canada; Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: James C
authors.initials: JC
authors.lastname: Engert
mesh_terms: D000293:Adolescent; D002648:Child; D015331:Cohort Studies; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics*; D044465:White People
chemical_list: D004298:Dopamine