title: Association of nicotinic acetylcholine receptor subunit alpha 4 polymorphisms with nicotine dependence in 5500 Germans.
abstract: Polymorphisms in the CHRNA4 gene coding the nicotinic acetylcholine receptor subunit alpha 4 have recently been suggested to play a role in the determination of smoking-related phenotypes. To examine this hypothesis, we conducted a genetic association study in three large samples from the German general population (N(1)=1412; N(2)=1855; N(3)=2294). Five single-nucleotide polymorphisms in CHRNA4 were genotyped in 5561 participants, including 2707 heavily smoking cases (regularly smoking at least 20 cigarettes per day) and 2399 never-smoking controls (<or=100 cigarettes over lifetime). We examined associations of the polymorphisms with smoking case-control status and with the extent of nicotine dependence as measured by the Fagerstrom test of nicotine dependence (FTND) score (N=1030). The most significant association was observed between rs2236196 and FTND (P=0.0023), whereas the closely linked rs1044396 had most statistical support in the case-control models (P=0.0080). The consistent effect estimates across three independent cohorts elaborate on recently published functional studies of rs2236196 from the CHRNA4 3'-untranslated region and seem to converge with accumulating evidence to firmly implicate the variant G allele of this polymorphism in the intensification of nicotine dependence.
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany. L.Breitling@dkfz.de
authors.forename: L P
authors.initials: LP
authors.lastname: Breitling
authors.forename: N
authors.initials: N
authors.lastname: Dahmen
authors.forename: K
authors.initials: K
authors.lastname: Mittelstrass
authors.forename: D
authors.initials: D
authors.lastname: Rujescu
authors.forename: J
authors.initials: J
authors.lastname: Gallinat
authors.forename: C
authors.initials: C
authors.lastname: Fehr
authors.forename: I
authors.initials: I
authors.lastname: Giegling
authors.forename: C
authors.initials: C
authors.lastname: Lamina
authors.forename: T
authors.initials: T
authors.lastname: Illig
authors.forename: H
authors.initials: H
authors.lastname: Müller
authors.forename: E
authors.initials: E
authors.lastname: Raum
authors.forename: D
authors.initials: D
authors.lastname: Rothenbacher
authors.forename: H-E
authors.initials: HE
authors.lastname: Wichmann
authors.forename: H
authors.initials: H
authors.lastname: Brenner
authors.forename: G
authors.initials: G
authors.lastname: Winterer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D016540:Smoking Cessation; D014029:Tobacco Use Disorder / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D011978:Receptors, Nicotinic