title: Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance.
abstract: Recent studies strongly support an association of the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 with nicotine dependence (ND). However, the precise genotype-phenotype relationship is still unknown. Clinical and epidemiological data on smoking behavior raise the possibility that the relevant gene variants may indirectly contribute to the development of ND by affecting cognitive performance in some smokers who consume nicotine for reasons of "cognition enhancement." Here, we tested seven single nucleotide polymorphisms (SNPs) rs684513, rs637137, rs16969968, rs578776, rs1051730, rs3743078, rs3813567 from the CHRNA5-CHRNA3-CHRNB4 gene cluster for association with ND, measures of cognitive performance and gene expression. As expected, we found all SNPs being associated with ND in three independent cohorts (KORA, NCOOP, ESTHER) comprising 5,561 individuals. In an overlapping sample of 2,186 subjects we found three SNPs (rs16969968, rs1051730, rs3743078) being associated with cognitive domains from the Wechsler-Adult-Intelligence Scale (WAIS-R)-most notably in the performance subtest "object assembly" and the verbal subtest "similarities." In a refined analysis of a subsample of 485 subjects, two of these three SNPs (rs16969968, rs1051730) were associated with n-back task performance/Continuous Performance Test. Furthermore, two CHRNA5 risk alleles (rs684513, rs637137) were associated with CHRNA5 mRNA expression levels in whole blood in a subgroup of 190 subjects. We here report for the first time an association of CHRNA5-CHRNA3-CHRNB4 gene variants with cognition possibly mediating in part risk for developing ND. The observed phenotype-genotype associations may depend on altered levels of gene expression. © 2010 Wiley-Liss, Inc.
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany. georg.winterer@uni-koeln.de
authors.forename: Georg
authors.initials: G
authors.lastname: Winterer
authors.forename: Kirstin
authors.initials: K
authors.lastname: Mittelstrass
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Claudia
authors.initials: C
authors.lastname: Lamina
authors.forename: Christoph
authors.initials: C
authors.lastname: Fehr
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Lutz P
authors.initials: LP
authors.lastname: Breitling
authors.forename: Barbara
authors.initials: B
authors.lastname: Nitz
authors.forename: Elke
authors.initials: E
authors.lastname: Raum
authors.forename: Heiko
authors.initials: H
authors.lastname: Müller
authors.forename: Jürgen
authors.initials: J
authors.lastname: Gallinat
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
authors.forename: Katharina
authors.initials: K
authors.lastname: Heim
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Annette M
authors.initials: AM
authors.lastname: Hartmann
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Möller
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Norbert
authors.initials: N
authors.lastname: Dahmen
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
mesh_terms: D000328:Adult; D000368:Aged; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003071:Cognition; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics*; D012306:Risk; D014029:Tobacco Use Disorder / Q000235:genetics*; D014888:Wechsler Scales
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human