A protocadherin gene cluster regulatory variant is associated with nicotine withdrawal and the urge to smoke.
- Authors
- Jensen, K P; Smith, A H; Herman, A I; Farrer, L A; Kranzler, H R; Sofuoglu, M; Gelernter, J
- Year
- 2017
- Journal
- Molecular psychiatry
- PMID
- 27067016
- DOI
- 10.1038/mp.2016.43
- PMCID
- PMC5390815
Nicotine withdrawal symptoms contribute to relapse in smokers, thereby prolonging the harm caused by smoking. To investigate the molecular basis for this phenomenon, we conducted a genome-wide association study of DSM-IV nicotine withdrawal in a sample of African American (AA) and European American (EA) smokers. A combined AA and EA meta-analysis (n=8021) identified three highly correlated single nucleotide polymorphisms (SNPs) in the protocadherin (PCDH)-α, -β and -γ gene cluster on chromosome 5 that were associated with nicotine withdrawal (P<5 × 10). We then studied one of the SNPs, rs31746, in an independent sample of smokers who participated in an intravenous nicotine infusion study that followed overnight smoking abstinence. After nicotine infusion, abstinent smokers with the withdrawal risk allele experienced greater alleviation of their urges to smoke, as assessed by the Brief Questionnaire on Smoking Urges (BQSU). Prior work has shown that the PCDH-α, -β and -γ genes are expressed in neurons in a highly organized manner. We found that rs31746 mapped to a long-range neuron-specific enhancer element shown previously to regulate PCDH-α, -β and -γ gene expression. Using Braincloud mRNA expression data, we identified a robust and specific association between rs31746 and PCDH-β8 mRNA expression in frontal cortex tissue (P<1 × 10). We conclude that PCDH-α, -β and -γ gene cluster regulatory variation influences the severity of nicotine withdrawal. Further studies on the PCDH-α, -β and -γ genes and their role in nicotine withdrawal may inform the development of novel smoking cessation treatments and reduce the harm caused by tobacco smoking.
A genomewide association study of nicotine withdrawal. A. A quantile-quantile plot of observed and expected P-values for a meta-analysis of nicotine withdrawal that included European American (EA) and African American (AA) subjects (n=8,021). The genomic inflation factor, λ, is the observed median test statistic divided by the expected median test statistic. B. A regional plot generated with LocusZoom (http://locuszoom.sph.umich.edu/locuszoom/) showing nicotine withdrawal associated SNPs in the protocadherin-α, -β and -γ gene cluster. The linkage disequilibrium (r2) is based on the 1000 Genomes Ad-mixed American sample (AMR).
Rs31746 is associated with nicotine withdrawal in European American (EA) and African American (AA) smokers. The odds ratio (± 95% confidence interval) for rs31746*A observed for six studies and for the combined fixed effects meta-analysis (Pmeta = 3.67 × 10−8; OR=1.2 [95% confidence interval=1.13–1.30]). For each sample, the size (n) and rs31746 A-allele frequency are shown.
The nicotine withdrawal risk allele, rs31746*A, is associated with a greater reduction in the urge to smoke following an intravenous nicotine infusion session. A. Mean Brief Questionnaire on Smoking Urges (BQSU) score pre- and post-administration of nicotine to smokers following overnight smoking abstinence. B. The average change in BQSU total, BQSU Factor 1 and BQSU Factor 2 scores for each genotype group. * p<0.05 for the genotype by treatment interaction. Error bars = ± standard error of the mean (SEM).
The position and regulatory effects of nicotine-withdrawal-associated variants in the protocadherin (PCDH)-α, -β, and -γ gene cluster. A. A modified UCSC Genome Browser (http://genome.ucsc.edu) image showing the position of the three nicotine-withdrawal-associated risk variants relative to a neuron-specific enhancer element (HS5-1a,b; green bars) and the DNA binding sites for CCCTC-binding factor (CTCF; black bars). ENCODE generated DNAseI hypersensitivity regions for frontal cortex (FC) DNA and fibroblast DNA are also shown. B. The association of rs31746 with PCDH-α, -β, and -γ gene mRNA expression in prefrontal cortex based on BrainCloud (http://braincloud.jhmi.edu). Each point represents an mRNA probe.
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