title: CHRNB3 is more strongly associated with Fagerström test for cigarette dependence-based nicotine dependence than cigarettes per day: phenotype definition changes genome-wide association studies results.
abstract: OBJECTIVE
  Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e., CPD versus Fagerström test for cigarette dependence (FTCD) score as a measure of nicotine dependence) on genome-wide association studies of nicotine dependence.
  
  
  METHODS
  Genome-wide association study.
  
  
  METHODS
  Community sample.
  
  
  METHODS
  A total of 3365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2267 were European Americans, 999 were African Americans.
  
  
  METHODS
  Nicotine dependence defined by FTCD score ≥4, CPD.
  
  
  RESULTS
  The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 [odds ratio (OR) = 0.65, P = 2.4 × 10(-8) ]. This association was further strengthened in a meta-analysis with a previously published data set (combined P = 6.7 × 10(-16) , total n = 4200). When CPD was used as an alternate phenotype, the association no longer reached genome-wide significance (β  =  -0.08, P = 0.0004).
  
  
  CONCLUSIONS
  Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence show different associations with polymorphisms in genetic loci.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA. john@zork.wustl.edu
authors.forename: John P
authors.initials: JP
authors.lastname: Rice
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Hartz
authors.forename: Arpana
authors.initials: A
authors.lastname: Agrawal
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.forename: Siiri
authors.initials: S
authors.lastname: Bennett
authors.forename: Naomi
authors.initials: N
authors.lastname: Breslau
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Bucholz
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Alison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Victor
authors.initials: V
authors.lastname: Hesselbrock
authors.forename: William B
authors.initials: WB
authors.lastname: Howells
authors.forename: Eric O
authors.initials: EO
authors.lastname: Johnson
authors.forename: John
authors.initials: J
authors.lastname: Kramer
authors.forename: Robert F
authors.initials: RF
authors.lastname: Krueger
authors.forename: Samuel
authors.initials: S
authors.lastname: Kuperman
authors.forename: Cathy
authors.initials: C
authors.lastname: Laurie
authors.forename: Teri A
authors.initials: TA
authors.lastname: Manolio
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Neuman
authors.forename: John I
authors.initials: JI
authors.lastname: Nurnberger
authors.forename: Bernice
authors.initials: B
authors.lastname: Porjesz
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Pugh
authors.forename: Erin M
authors.initials: EM
authors.lastname: Ramos
authors.forename: Nancy
authors.initials: N
authors.lastname: Saccone
authors.forename: Scott
authors.initials: S
authors.lastname: Saccone
authors.forename: Marc
authors.initials: M
authors.lastname: Schuckit
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D062789:Tobacco Products; D014029:Tobacco Use Disorder / Q000175:diagnosis / Q000235:genetics*
chemical_list: C539371:CHRNB3 protein, human; D011978:Receptors, Nicotinic