Molecular genetics of successful smoking cessation: convergent genome-wide association study results

Abstract

Context: Smoking remains a major public health problem. Twin studies indicate that the ability to quit smoking is substantially heritable, with genetics that overlap modestly with the genetics of vulnerability to dependence on addictive substances.

Objectives: To identify replicated genes that facilitate smokers' abilities to achieve and sustain abstinence from smoking (herein after referred to as quit-success genes) found in more than 2 genome-wide association (GWA) studies of successful vs unsuccessful abstainers, and, secondarily, to nominate genes for selective involvement in smoking cessation success with bupropion hydrochloride vs nicotine replacement therapy (NRT).

Design: The GWA results in subjects from 3 centers, with secondary analyses of NRT vs bupropion responders.

Setting: Outpatient smoking cessation trial participants from 3 centers.

Participants: European American smokers who successfully vs unsuccessfully abstain from smoking with biochemical confirmation in a smoking cessation trial using NRT, bupropion, or placebo (N = 550).

Main outcome measures: Quit-success genes, reproducibly identified by clustered nominally positive single-nucleotide polymorphisms (SNPs) in more than 2 independent samples with significant P values based on Monte Carlo simulation trials. The NRT-selective genes were nominated by clustered SNPs that display much larger t values for NRT vs placebo comparisons. The bupropion-selective genes were nominated by bupropion-selective results.

Results: Variants in quit-success genes are likely to alter cell adhesion, enzymatic, transcriptional, structural, and DNA, RNA, and/or protein-handling functions. Quit-success genes are identified by clustered nominally positive SNPs from more than 2 samples and are unlikely to represent chance observations (Monte Carlo P< .0003). These genes display modest overlap with genes identified in GWA studies of dependence on addictive substances and memory.

Conclusions: These results support polygenic genetics for success in abstaining from smoking, overlap with genetics of substance dependence and memory, and nominate gene variants for selective influences on therapeutic responses to bupropion vs NRT. Molecular genetics should help match the types and/or intensity of antismoking treatments with the smokers most likely to benefit from them.

Figure 1

Scatterplot of the distributions of t values for comparisons between individuals with successful vs unsuccessful attempts to quit smoking in pooled samples from those receiving nicotine replacement therapy (NRT) (x-axis) vs bupropion hydrochloride (y-axis) for secondary analyses seeking candidate genes with treatment-specific effects. If no genes provided treatment-specific effects, values would cluster on a 45° line from the origin. We highlight single-nucleotide polymorphisms (SNPs) that provide NRT-selective (pink shading) or bupropion-selective (blue shading) effects (see also eTable 4). The t values of 3.6 and 3.7 for NRT and bupropion, respectively, correspond to P < .005. These data combine individuals from samples 1 and 2 who received NRT and individuals from samples 1 and 3 who received bupropion.

Figure 2

Distributions of data from the present study mapped onto cartoons of human chromosomes 1 through 10 (top row), 11 through 17 (second row), and 18 through 22 (third row). Blue dots to the left of the (black) main axis for each chromosome represent the t values for all single-nucleotide polymorphisms (SNPs) in the comparison of allele frequencies in individuals with successful vs unsuccessful attempts to quit smoking from sample 1 with the chromosomal position of each corresponding SNP. Red dots to the right of the (black) main axis for each chromosome mark sites for clustered positive SNPs from sample 1 for which successful vs unsuccessful abstainer differences display P < .01, lie within 0.1 megabase (Mb) of at least 1 other SNP that displays P < .01, and cluster so that at least 3 clustered outlier SNPs from 2 array types (StyI, NspI) are found in the cluster. Green dots to the right of the black main axis for each chromosome mark sites for clustered positive SNPs from sample 2 for which successful vs unsuccessful abstainer differences display P < .01, lie within 0.1 Mb of at least 1 other SNP that displays P < .01, and cluster so that at least 2 clustered outlier SNPs are found in the cluster. Black dots to the right of the black main axis for each chromosome mark sites for clustered positive SNPs from sample 3 for which successful vs unsuccessful abstainer differences display P < .01, lie within 0.1 Mb of at least 1 other SNP that displays P < .01, and cluster so that at least 2 clustered outlier SNPs are found in the cluster. Yellow triangles to the right of the black main axis for each chromosome mark sites for genes identified by clustered positive SNPs from at least 2 samples (see the Table). Chromosomal positions are based on National Center for Biotechnology Information Map Viewer Build 36.1 coordinates (http://www.ncbi.nlm.nih.gov/mapview/) and supplemental data from NetAffx Analysis Center (http://www.science.fau.edu/genechip/NetAffx_analysis_center.html).