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.

Cognitive Effects of Nicotine

“…In a recent study, Winterer et al (2010) found a significant association between a functional variant, rs16969968, of the gene that encodes the a5 subunit of nAChRs (CHRNA5) and performance on the N-back working memory task that is consistent with the results of the aforementioned preclinical studies. The rs16969968 SNP has been associated with the age at which an individual initiates cigarette smoking, the severity of the nicotine dependence as measured by the Fagerström Test for Nicotine Dependence score, and the number of cigarettes that an individual smokes each day (Berrettini et al, 2008;Bierut et al, 2007;Saccone et al, 2007;Winterer et al, 2010).…”

“…The rs16969968 SNP has been associated with the age at which an individual initiates cigarette smoking, the severity of the nicotine dependence as measured by the Fagerström Test for Nicotine Dependence score, and the number of cigarettes that an individual smokes each day (Berrettini et al, 2008;Bierut et al, 2007;Saccone et al, 2007;Winterer et al, 2010). These findings suggest that the vulnerability to nicotine dependence that is associated with this particular SNP may be mediated by a reduction in the cognitive performance of the individual.…”

“…These findings suggest that the vulnerability to nicotine dependence that is associated with this particular SNP may be mediated by a reduction in the cognitive performance of the individual. Thus, individuals with baseline cognitive impairments may be more vulnerable to nicotine dependence for the cognitive-enhancing effects of nicotine (Winterer et al, 2010).…”

“…These findings suggest that these deficits existed in some individuals before they began smoking. Further, Winterer et al (2010) found that a genetic variation in the α5 nAChR may increase the degree to which an individual is vulnerable to nicotine dependence and may be associated with reduced performance on a working memory task. Presumably, individuals with genetic vulnerability may derive particular benefit from the cognitive-enhancing effects of nicotine (Winterer et al, 2010).…”

A genetic variant within STS previously associated with inattention in boys with attention deficit hyperactivity disorder is associated with enhanced cognition in healthy adult males

“…Males from Cohort 2 underwent a battery of cognitive tasks (Winterer et al., 2010), of which the Continuous Performance Task (CPT) was most relevant to understanding attention. Key measures that were available from this sample included number of hits (i.e., responses to targets), false alarms (responses to non‐targets), and perceptual sensitivity ( D ′).…”