title: A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans.
abstract: Genome-wide association studies have implicated the CHRNA5-CHRNA3-CHRNB4 gene cluster in risk for heavy smoking and several smoking-related disorders. The heavy smoking risk allele might reduce the aversive effects of nicotine, but this hypothesis has not been tested in humans. We evaluated the effects of a candidate causal variant in CHRNA5, rs16969968, on the acute response to nicotine in European American (EA) and African American (AA) smokers (n=192; 50% AA; 73% male). Following overnight abstinence from nicotine, participants completed a protocol that included an intravenous (IV) dose of saline and two escalating IV doses of nicotine. The outcomes evaluated were the aversive, pleasurable, and stimulatory ratings of nicotine's effects, cardiovascular reactivity to nicotine, withdrawal severity, and cognitive performance before and after the nicotine administration session. The heavy smoking risk allele (rs16969968*A; frequency=28% (EA) and 6% (AA)) was associated with lower ratings of aversive effects (P<5 × 10(-8)) with marked specificity. This effect was evident in EA and AA subjects analyzed as separate groups and was most robust at the highest nicotine dose. Rs16969968*A was also associated with greater improvement on a measure of cognitive control (Stroop Task) following nicotine administration. These findings support differential aversive response to nicotine as one likely mechanism for the association of CHRNA5-CHRNA3-CHRNB4 with heavy smoking.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.|VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Jensen
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.|VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: Elise E
authors.initials: EE
authors.lastname: DeVito
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.|VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: Aryeh I
authors.initials: AI
authors.lastname: Herman
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.|VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Valentine
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.|VA Connecticut Healthcare System, West Haven, CT, USA.|Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.|Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.|VA Connecticut Healthcare System, West Haven, CT, USA.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Sofuoglu
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000209:etiology; D003367:Cotinine / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D055106:Genome-Wide Association Study; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009483:Neuropsychological Tests; D009538:Nicotine / Q000009:adverse effects* / Q000097:blood; D018722:Nicotinic Agonists / Q000009:adverse effects* / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000503:physiopathology / Q000523:psychology; D011795:Surveys and Questionnaires
chemical_list: C447158:CHRNA5 protein, human; D009419:Nerve Tissue Proteins; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C001381:hydroxycotinine; D009538:Nicotine; D003367:Cotinine