Article

Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance

Cologne Center for Genomics, University of Cologne, Cologne, Germany.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.27). 12/2010; 153B(8):1448-58. DOI: 10.1002/ajmg.b.31126
Source: PubMed

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.

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    • "Furthermore, it has been associated in vitro with lower agonist-evoked intracellular calcium response of α4β2α5 nAChRs, lower Ca2+ permeability and greater short-term desensitization compared to the α5 ancestral allele (G) [55], [59]. Moreover, the A allele has also been associated with increased risk for lung cancer [55], nicotine dependence and smoking behavior [60], [61], as well as with lower cognitive performance in healthy subjects [62]. More recently, two studies have demonstrated that this allele is also associated with increased susceptibility to schizophrenia and bipolar disorders [63], [64]. "
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    • "The observed interaction effect helps to reveal that not all individuals who were high in ADHD symptoms also reported problems with smoking. Researchers have suggested that certain aspects of neurocognitive functioning , such as sustained attention (Greenbaum & Lerer, 2009; Rigbi et al., 2008; Russo et al., 2011; Ware et al., 2011; Winterer et al., 2010; Zhang et al., 2010), could be a potential mechanism for both smoking vulnerability and components of the ADHD phenotype. Also, variation in subunits of the nAChRs, including rs13280604, plays a role in dopamine modulation which may affect ADHD symptoms and reinforce cigarette usage (Zeiger et al., 2008). "
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    • "Such differential responses are consistent with the notion that nAChR stimulation most robustly improves behavior in individuals performing sub-optimally (Newhouse et al., 2004). Behavioral performance appears mediated by genetic influences on nAChR function (Greenwood et al., 2012; Winterer et al., 2010) and, when assessed during early abstinence, predicts smoking relapse (Patterson et al., 2010). "
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