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Convergent Genome-Wide Association Study Results

George R. Uhl, MD, PhD; Qing-Rong Liu, PhD; Tomas Drgon, PhD; Catherine Johnson, MSc; Donna Walther, MSc; Jed E. Rose, PhD; Sean P. David, MD; Ray Niaura, PhD; Caryn Lerman, PhD

Arch Gen Psychiatry. 2008;65(6):683-693.

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 (hereinafter 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.

Author Affiliations: Molecular Neurobiology Branch, National Institutes of Health–Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland (Drs Uhl, Liu, and Drgon and Mss Johnson and Walther); Department of Psychiatry and Behavioral Sciences and Center for Nicotine and Smoking Cessation Research, Duke University, Durham, North Carolina (Dr Rose); Departments of Family Medicine (Dr David) and Psychiatry and Human Behavior (Dr Niaura), Warren Alpert Medical School, Brown University, Pawtucket, Rhode Island; Transdisciplinary Research Group, Butler Hospital, Providence, Rhode Island (Dr Niaura); and Tobacco Use Research Center, Department of Psychiatry and Abramson Cancer Center, University of Pennsylvania, Philadelphia (Dr Lerman).