Replicated association of the NR4A3 gene with smoking behaviour in schizophrenia and in bipolar disorder

Novak, G.; Zai, C. C.; Mirkhani, M.; Shaikh, S.; Vincent, J. B.; Meltzer, H.; Lieberman, J. A.; Strauss, J.; Lévesque, D.; Kennedy, J. L.; Le Foll, B.

doi:10.1111/j.1601-183x.2010.00631.x

Cited by 23Smoking Behavior and CessationSchizophrenia research and treatmentGenetic Associations and Epidemiology

Replicated association of the NR4A3 gene with smoking behaviour in schizophrenia and in bipolar disorder

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Novak, G., Zai, C. C., Mirkhani, M., Shaikh, S., Vincent, J. B., Meltzer, H., Lieberman, J. A., Strauss, J. +3 more·2010·Genes, Brain and Behavior

DOI 10.1111/j.1601-183x.2010.00631.x

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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.

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There is a genetic predisposition in a subgroup of people with bipolar disorder for tobacco use disorder.
“This finding suggests that there is a genetic predisposition in a subgroup of people with BD for TUD.”
From The detrimental effects of smoking on the course and outcome in adults with bipolar disorder—A narrative review (2023) · cites this paper as [21]
The NR4A3 marker rs1131339 is significantly associated with the risk of smoker status and with the degree of smoking in people with bipolar disorder.
“Association analysis of marker allele of the NR4A3 marker rs1131339 with smoking behavior in people with BD demonstrated a significant association with the risk of smoker status (smokers compared to non-smokers) as well as with the degree of smoking (21).”
From The detrimental effects of smoking on the course and outcome in adults with bipolar disorder—A narrative review (2023) · cites this paper as [21]

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Slyepchenko, A., Brunoni, A. R., McIntyre, R. S., Quevedo, J., & Carvalho, A. F. (2016) · Current Molecular Medicine · doi:10.2174/1566524016666160126144601 · Cited by 14 · see citing works
Smoking is Associated with Greater Symptom Load in Bipolar Disorder Patients
Saiyad, M., & El-Mallakh, R. S. (2012) · Annals of Clinical Psychiatry · doi:10.1177/104012371202400409 · Cited by 13 · see citing works
The detrimental effects of smoking on the course and outcome in adults with bipolar disorder—A narrative review
Grunze, A., Mosolov, S., Grunze, H., & Born, C. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.1114432 · Cited by 11 · see citing works
“However, with respect to BD, a single nucleotide polymorphism (SNPs) of the NR4A3 gene was found of special interest in another study (21) as it has a decisive role in the modulation of the dopaminergic responsiveness within the meso-cortical system.”
Background
Association between NR4A2 genetic variation and schizophrenia: A comprehensive systematic review and meta-analysis
Liu, H., Fu, Y., Ren, J., Yu, S., Liu, H., Jiang, P., Dong, Y. W., & Li, H. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.05.018 · Cited by 11 · see citing works
A Systematic Review of Genetic Polymorphisms Associated with Bipolar Disorder Comorbid to Substance Abuse
de Marco, A., Scozia, G., Manfredi, L., & Conversi, D. (2022) · Genes · doi:10.3390/genes13081303 · Cited by 10 · see citing works
Aberrant DNA Methylation Pattern may Enhance Susceptibility to Migraine: A Novel Perspective
Goel, D., Nisa, K. U., Reza, M. I., Rahman, Z., & Aamer, S. (2019) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527318666190809162631 · Cited by 10 · see citing works
Localization of nuclear receptor subfamily 4, group A, member 3 ( NR4A3 ) in L ewy body disease and multiple system atrophy
Kon, T., Miki, Y., Tanji, K., Mori, F., Tomiyama, M., Toyoshima, Y., Kakita, A., Takahashi, H., Utsumi, J., Sasaki, H., et al. (2015) · Neuropathology · doi:10.1111/neup.12210 · Cited by 9 · see citing works
The impact of smoke-free policies on inpatient psychiatric units : an ethnographic study
Grant, L. G. (2013) · cIRcle (University of British Columbia) · doi:10.14288/1.0073609
Cracking the Code of Neuronal Cell Fate
Morello, G., Cognata, V. L., Guarnaccia, M., D’Agata, V., & Cavallaro, S. (2023) · Cells · doi:10.3390/cells12071057

Association of a polymorphism in the NRXN3 gene with the degree of smoking in schizophrenia: A preliminary study
Novak, G., Boukhadra, J., Shaikh, S. A., Kennedy, J. L., & Foll, B. L. (2009) · The World Journal of Biological Psychiatry · doi:10.1080/15622970903079499 · Cited by 46 · see citing works
Self-citation
Association of polymorphisms in the BDNF, DRD1 and DRD3 genes with tobacco smoking in schizophrenia
Novak, G., LeBlanc, M., Zai, C. C. H., Shaikh, S. A., Renou, J., Luca, V. D., Bulgin, N., Kennedy, J. L., & Foll, B. L. (2010) · Annals of Human Genetics · doi:10.1111/j.1469-1809.2010.00578.x · Cited by 60 · see citing works
Self-citation
Genetic Variation of the Mu Opioid Receptor (OPRM1) and Dopamine D2 Receptor (DRD2) is Related to Smoking Differences in Patients with Schizophrenia but not Bipolar Disorder
Hirasawa-Fujita, M., Bly, M. J., Ellingrod, V. L., Dalack, G. W., & Domino, E. F. (2017) · Clinical Schizophrenia & Related Psychoses · doi:10.3371/1935-1232-11.1.39 · Cited by 35 · see citing works
Association of α4β2 nicotinic receptor and heavy smoking in schizophrenia
Voineskos, S. H., Luca, V. D., Mensah, A. K., Vincent, J. B., Potapova, N., & Kennedy, J. L. (2007) · Journal of Psychiatry and Neuroscience · doi:10.1139/jpn.0740 · Cited by 36 · see citing works
Self-citation
Dopamine DRD2 and DRD3 Polymorphisms Involvement in Nicotine Dependence in Patients with Treatment-Resistant Mental Disorders
CASALE, A. D., Paolini, M., Gentile, G., Borro, M., Zocchi, C., Fiaschè, F., Padovano, A., Zoppi, T., Modesti, M. N., Luca, O. D., et al. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12040565 · Cited by 12 · see citing works

Authors: Novak, G., Zai, C. C., Mirkhani, M., Shaikh, S., Vincent, J. B., Meltzer, H., Lieberman, J. A., Strauss, J., Lévesque, D., Kennedy, J. L., & Le Foll, B.
Affiliations: Centre for Addiction and Mental Health (CA)
Vanderbilt University (US)
New York State Psychiatric Institute (US)
Université de Montréal (CA)
Corresponding author: Kennedy, J. L.
ORCID: Novak, G.
Zai, C. C.
Shaikh, S.
Vincent, J. B.
Meltzer, H.
Lieberman, J. A.
Lévesque, D.
Kennedy, J. L.
Venue: Genes, Brain and Behavior
Publisher: Wiley
Published: 2010-11
Volume: 9
Issue: 8
Pages: 910-917
ISSN: 1601-183X (ISSN-L)
1601-1848
DOI: 10.1111/j.1601-183x.2010.00631.x
OpenAlex: W2091670456
Cited by: 23
References: 63
Citations by year: 2024: 1 · 2023: 5 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 4 · 2013: 2 · 2012: 2
FWCI: 1.30
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3 d)
Locations: Genes Brain & Behavior (publishedVersion)
PubMed (publishedVersion)
Funders: GlaxoSmithKline
Canadian Institutes of Health Research
Topics: Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords: NR4A3, smoking behavior, schizophrenia, bipolar disorder, nicotine dependence, single nucleotide polymorphisms, dopamine signaling, replication
MeSH terms: Adult, Bipolar Disorder, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, Receptors, Steroid, Receptors, Thyroid Hormone, Reference Values, Risk Factors, Schizophrenia, Smoking, Tobacco Use Disorder, Case-Control Studies, Matched-Pair Analysis, Diagnosis, Dual (Psychiatry)

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Replicated association of the NR4A3 gene with smoking behaviour in schizophrenia and in bipolar disorder

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