Chromosome 20 Shows Linkage With DSM-IV Nicotine Dependence in Finnish Adult Smokers

Keskitalo-Vuokko, Kaisu; Hällfors, Jenni; Broms, Ulla; Pergadia, Michele L.; Saccone, Scott F.; Loukola, Anu; Madden, Pamela A. F.; Kaprio, Jaakko

doi:10.1093/ntr/ntr153

Cited by 2 publications

(3 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genome-wide significant linkage signals have been observed in the chromosome 20q13 region containing CHRNA4 for maximum number of cigarettes smoked in a 24-h period 74 and in the nearby chromosome 20q11 region for DSM-IV-defined nicotine dependence. 75 Several candidate gene association studies have focused on CHRNA4 . 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 Among the common SNPs with reported associations, only rs2236196 was associated in our study ( P =0.027, Table 3 ): its minor allele (frequency=0.28) conferring increased risk for nicotine dependence, consistent with prior reports.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence

et al. 2015

View full text Add to dashboard Cite

We conducted a 1000 Genomes–imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10−9 across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08–1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10−4). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00–1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single ‘cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.

show abstract

Section: Discussionmentioning

confidence: 99%

Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence

et al. 2015

View full text Add to dashboard Cite

show abstract

“…NNAT is one of the genes located in this region. Although this study [53] did not specifically assess polymorphisms in the NNAT gene, our data show that Nnat is potentially involved in driving the linkage of this chromosomal region with nicotine dependence (i.e., at least in women).…”

Section: Discussionmentioning

confidence: 80%

“…Developmentally regulated, Nnat is highly expressed during neurogenesis [70] , and it may influence site-specific synaptic events such as long-term potentiation or depression by modulating local dendritic calcium levels [71] . Perhaps most importantly, a recent genetic linkage study, using DSM-IV criteria, identified chromosome 20q11.23 as a locus harboring genetic variations linked to nicotine dependence [53] . NNAT is one of the genes located in this region.…”

Section: Discussionmentioning

confidence: 99%

Protection Genes in Nucleus Accumbens Shell Affect Vulnerability to Nicotine Self-Administration across Isogenic Strains of Adolescent Rat

et al. 2014

View full text Add to dashboard Cite

Classical genetic studies show the heritability of cigarette smoking is 0.4–0.6, and that multiple genes confer susceptibility and resistance to smoking. Despite recent advances in identifying genes associated with smoking behaviors, the major source of this heritability and its impact on susceptibility and resistance are largely unknown. Operant self-administration (SA) of intravenous nicotine is an established model for smoking behavior. We recently confirmed that genetic factors exert strong control over nicotine intake in isogenic rat strains. Because the processing of afferent dopaminergic signals by nucleus accumbens shell (AcbS) is critical for acquisition and maintenance of motivated behaviors reinforced by nicotine, we hypothesized that differential basal gene expression in AcbS accounts for much of the strain-to-strain variation in nicotine SA. We therefore sequenced the transcriptome of AcbS samples obtained by laser capture microdissection from 10 isogenic adolescent rat strains and compared all RNA transcript levels with behavior. Weighted gene co-expression network analysis, a systems biology method, found 12 modules (i.e., unique sets of genes that covary across all samples) that correlated (p<0.05) with amount of self-administered nicotine; 9 of 12 correlated negatively, implying a protective role. PCR confirmed selected genes from these modules. Chilibot, a literature mining tool, identified 15 genes within 1 module that were nominally associated with cigarette smoking, thereby providing strong support for the analytical approach. This is the first report demonstrating that nicotine intake by adolescent rodents is associated with the expression of specific genes in AcbS of the mesolimbic system, which controls motivated behaviors. These findings provide new insights into genetic mechanisms that predispose or protect against tobacco addiction.

show abstract

Chromosome 20 Shows Linkage With DSM-IV Nicotine Dependence in Finnish Adult Smokers

Cited by 2 publications

References 29 publications

Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence

Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence

Protection Genes in Nucleus Accumbens Shell Affect Vulnerability to Nicotine Self-Administration across Isogenic Strains of Adolescent Rat

Contact Info

Product

Resources

About