title: Replicated association of the NR4A3 gene with smoking behaviour in schizophrenia and in bipolar disorder.
abstract: Schizophrenia and bipolar disorder are associated with dopamine neurotransmission and show high comorbidity with tobacco dependence. Recent evidence indicates that the family of the NR4A orphan nuclear receptors, which are expressed in dopamine neurons and in dopaminoceptive brain areas, may play a role in dopamine-mediated effects. We have, therefore, analysed the association of six single nucleotide polymorphisms (SNPs) within the three genes belonging to the NR4A orphan nuclear receptor family, NR4A1 (rs2603751, rs2701124), NR4A2 (rs12803, rs834835) and NR4A3 (rs1131339, rs1405209), with the degree of smoking in a sample of 204 unrelated schizophrenia patients, which included 126 smokers and 78 non-smokers. SNPs within the NR4A3 gene (rs1131339 and rs1405209) were significantly associated with heavy smoking in this cohort, using a stepwise analysis of the escalated number of cigarettes smoked per day (P = 0.008 and 0.006, respectively; satisfying the Nyholt significance threshold of 0.009, an adjustment for multiple testing). We then repeated the association analysis of the NR4A3 markers (rs1131339 and rs1405209) in a larger cohort of 319 patients with bipolar disorder, which included 167 smokers and 152 non-smokers. We have replicated the positive association with smoking of the NR4A3 SNP rs1131339 in this group (P = 0.04), providing an important confirmation of the involvement of the NR4A3 gene in nicotine addiction in patients with mental health disease, a population significantly at risk for nicotine addiction.
authors.affiliation: Neuroscience Research Department, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Novak
authors.forename: C C
authors.initials: CC
authors.lastname: Zai
authors.forename: M
authors.initials: M
authors.lastname: Mirkhani
authors.forename: S
authors.initials: S
authors.lastname: Shaikh
authors.forename: J B
authors.initials: JB
authors.lastname: Vincent
authors.forename: H
authors.initials: H
authors.lastname: Meltzer
authors.forename: J A
authors.initials: JA
authors.lastname: Lieberman
authors.forename: J
authors.initials: J
authors.lastname: Strauss
authors.forename: D
authors.initials: D
authors.lastname: Lévesque
authors.forename: J L
authors.initials: JL
authors.lastname: Kennedy
authors.forename: B
authors.initials: B
authors.lastname: Le Foll
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000150:complications / Q000235:genetics*; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D017831:Diagnosis, Dual (Psychiatry); D005260:Female; D006801:Humans; D008297:Male; D016555:Matched-Pair Analysis; D008875:Middle Aged; D011987:Receptors, Steroid / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D012016:Reference Values; D012307:Risk Factors; D012559:Schizophrenia / Q000150:complications / Q000235:genetics*; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000150:complications / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C490412:NR4A3 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone