A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence.
paper
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- Authors
- Grucza, Richard A; Wang, Jen C; Stitzel, Jerry A; Hinrichs, Anthony L; Saccone, Scott F; Saccone, Nancy L; Bucholz, Kathleen K; Cloninger, C Robert; Neuman, Rosalind J; Budde, John P; Fox, Louis; Bertelsen, Sarah; Kramer, John; Hesselbrock, Victor; Tischfield, Jay; Nurnberger, John I; Almasy, Laura; Porjesz, Bernice; Kuperman, Samuel; Schuckit, Marc A; Edenberg, Howard J; Rice, John P; Goate, Alison M; Bierut, Laura J
- Year
- 2008
- Journal
- Biological psychiatry
- PMID
- 18519132
- DOI
- 10.1016/j.biopsych.2008.04.018
- PMCID
- PMC2582594
BACKGROUND: A nonsynonymous coding polymorphism, rs16969968, of the CHRNA5 gene that encodes the alpha-5 subunit of the nicotinic acetylcholine receptor (nAChR) has been found to be associated with nicotine dependence. The goal of this study was to examine the association of this variant with cocaine dependence. METHODS: Genetic association analysis was performed in two independent samples of unrelated case and control subjects: 1) 504 European Americans participating in the Family Study on Cocaine Dependence (FSCD) and 2) 814 European Americans participating in the Collaborative Study on the Genetics of Alcoholism (COGA). RESULTS: In the FSCD, there was a significant association between the CHRNA5 variant and cocaine dependence (odds ratio = .67 per allele, p = .0045, assuming an additive genetic model), but in the reverse direction compared with that previously observed for nicotine dependence. In multivariate analyses that controlled for the effects of nicotine dependence, both the protective effect for cocaine dependence and the previously documented risk effect for nicotine dependence were statistically significant. The protective effect for cocaine dependence was replicated in the COGA sample. In COGA, effect sizes for habitual smoking, a proxy phenotype for nicotine dependence, were consistent with those observed in FSCD. CONCLUSIONS: The minor (A) allele of rs16969968, relative to the major G allele, appears to be both a risk factor for nicotine dependence and a protective factor for cocaine dependence. The biological plausibility of such a bidirectional association stems from the involvement of nAChRs with both excitatory and inhibitory modulation of dopamine-mediated reward pathways.
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| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Biochemical Diagnosis in Substance and Non-substance Addiction. | Shen W et al. | β | 2025 | β |
| Linking altered neuronal and synaptic properties to nicotinic receptor Alpha5 subunit gene dysfunction: a translational investigation in rat mPFC and human cortical layer 6. | Yang D et al. | β | 2025 | β |
| The influence of CHRNA5 and D398N missense variation on social and emotional behaviors in rodents and humans. | de Chaumont F et al. | β | 2025 | β |
| Analogs of Ξ±-conotoxin PnIC selectively inhibit Ξ±7Ξ²2- over Ξ±7-only subtype nicotinic acetylcholine receptors via a novel allosteric mechanism. | George AA et al. | β | 2024 | β |
| Distinct Chrna5 mutations link excessive alcohol use to types I/II vulnerability profiles and IPN GABAergic neurons. | Tochon L et al. | β | 2024 | β |
| Exploring the efficacy of cholinergic agents for the treatment of psychostimulant use disorder: a systematic review. | Salloum N et al. | β | 2024 | β |
| Generalized genetic liability to substance use disorders. | Miller AP et al. | β | 2024 | β |
| Investigating CHRNA5, CHRNA3, and CHRNB4 variants in the genetic landscape of substance use disorder in Jordan. | Al-Eitan L et al. | β | 2024 | β |
| Smoking-Related Increases in Alcohol Outcomes and Preliminary Evidence for the Protective Effect of a Functional Nicotine Receptor Gene (CHRNA5) Variant on Alcohol Consumption in Individuals Without Alcohol Use Disorder. | Venkatesh SK et al. | β | 2024 | β |
| Genotype-by-diagnosis interaction influences self-control in human cocaine addiction. | Graczyk MM et al. | β | 2023 | β |
| Molecular genetics of cocaine use disorders in humans. | FernΓ ndez-Castillo N et al. | β | 2022 | β |
| Neurobiological Mechanisms of Nicotine Reward and Aversion. | Wills L et al. | β | 2022 | β |
| Addiction-related neuroadaptations following chronic nicotine exposure. | Wills L et al. | β | 2021 | β |
| Alterations in nicotinic receptor alpha5 subunit gene differentially impact early and later stages of cocaine addiction: a translational study in transgenic rats and patients. | Forget B et al. | β | 2021 | β |
| Identification of the Risk Genes Associated With Vulnerability to Addiction: Major Findings From Transgenic Animals. | Jordan CJ et al. | β | 2021 | β |
| Linking the CHRNA5 SNP to drug abuse liability: From circuitry to cellular mechanisms. | Brynildsen JK et al. | β | 2021 | β |
| Mechanisms of Nicotine Addiction. | Picciotto MR et al. | β | 2021 | β |
| Cholinergic Receptors and Addiction. | Papke RL et al. | β | 2020 | β |
| Genetic Architecture and Molecular Neuropathology of Human Cocaine Addiction. | Huggett SB et al. | β | 2020 | β |
| Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution. | Icick R et al. | β | 2020 | β |
| The nicotinic receptor alpha5 coding polymorphism rs16969968 as a major target in disease: Functional dissection and remaining challenges. | Maskos U | β | 2020 | β |
| The Ξ±5 Nicotinic Acetylcholine Receptor Subunit Differentially Modulates Ξ±4Ξ²2<sup>*</sup> and Ξ±3Ξ²4<sup>*</sup> Receptors. | Scholze P et al. | β | 2020 | β |
| Relationship of common variants in CHRNA5 with early-onset schizophrenia and executive function. | Han W et al. | β | 2019 | β |
| The Role of the Medial Habenula Cholinergic System in Addiction and Emotion-Associated Behaviors. | Lee HW et al. | β | 2019 | β |
| Environmental, genetic and epigenetic contributions to cocaine addiction. | Pierce RC et al. | β | 2018 | β |
| Functional Neurocircuits and Neuroimaging Biomarkers of Tobacco Use Disorder. | Sutherland MT et al. | β | 2018 | β |
| Informing Prevention and Intervention Policy Using Genetic Studies of Resistance. | Maher BS et al. | β | 2018 | β |
| Neural and psychological characteristics of college students with alcoholic parents differ depending on current alcohol use. | Brown-Rice KA et al. | β | 2018 | β |
| Biochemical Diagnosis in Substance and Non-substance Addiction. | Shen W et al. | β | 2017 | β |
| Increased habenular connectivity in opioid users is associated with an Ξ±5 subunit nicotinic receptor genetic variant. | Curtis K et al. | β | 2017 | β |
| Isoform-specific mechanisms of Ξ±3Ξ²4*-nicotinic acetylcholine receptor modulation by the prototoxin lynx1. | George AA et al. | β | 2017 | β |
| Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse. | Cross SJ et al. | β | 2017 | β |
| SNP rs16969968 as a Strong Predictor of Nicotine Dependence and Lung Cancer Risk in a North Indian Population | Pandey N et al. | β | 2017 | β |
| The genetic epidemiology of substance use disorder: A review. | Prom-Wormley EC et al. | β | 2017 | β |
| African-specific variability in the acetylcholine muscarinic receptor M4: association with cocaine and heroin addiction. | Levran O et al. | β | 2016 | β |
| Alterations in alpha5* nicotinic acetylcholine receptors result in midbrain- and hippocampus-dependent behavioural and neural impairments. | Besson M et al. | β | 2016 | β |
| Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts. | Schwantes-An TH et al. | β | 2016 | β |
| Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence. | Kamens HM et al. | β | 2016 | β |
| KAT2B polymorphism identified for drug abuse in African Americans with regulatory links to drug abuse pathways in human prefrontal cortex. | Johnson EO et al. | β | 2016 | β |
| Nicotinic acetylcholine receptors: upregulation, age-related effects and associations with drug use. | Melroy-Greif WE et al. | β | 2016 | β |
| A multiancestry study identifies novel genetic associations with CHRNA5 methylation in human brain and risk of nicotine dependence. | Hancock DB et al. | β | 2015 | β |
| A powerful nonparametric statistical framework for family-based association analyses. | Li M et al. | β | 2015 | β |
| Common single nucleotide variants underlying drug addiction: more than a decade of research. | BΓΌhler KM et al. | β | 2015 | β |
| Genetic influences on nicotinic Ξ±5 receptor (CHRNA5) CpG methylation and mRNA expression in brain and adipose tissue. | Ramsay JE et al. | β | 2015 | β |
| Genomewide Association Study for Maximum Number of Alcoholic Drinks in European Americans and African Americans. | Xu K et al. | β | 2015 | β |
| Positive Selection on Loci Associated with Drug and Alcohol Dependence. | Sadler B et al. | β | 2015 | β |
| The habenulo-interpeduncular pathway in nicotine aversion and withdrawal. | Antolin-Fontes B et al. | β | 2015 | β |
| ADHD diagnosis may influence the association between polymorphisms in nicotinic acetylcholine receptor genes and tobacco smoking. | Polina ER et al. | β | 2014 | β |
| Association and interaction analyses of 5-HT3 receptor and serotonin transporter genes with alcohol, cocaine, and nicotine dependence using the SAGE data. | Yang J et al. | β | 2014 | β |
| Genetics of alcoholism. | Iyer-Eimerbrink PA et al. | β | 2014 | β |
| Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans. | Culverhouse RC et al. | β | 2014 | β |
| Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability. | Fowler CD et al. | β | 2014 | β |
| Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence. | Haller G et al. | β | 2014 | β |
| Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers. | Taylor AE et al. | β | 2014 | β |
| The role of the habenula in drug addiction. | Velasquez KM et al. | β | 2014 | β |
| Variants near CHRNB3-CHRNA6 are associated with DSM-5 cocaine use disorder: evidence for pleiotropy. | Sadler B et al. | β | 2014 | β |
| A bivariate mann-whitney approach for unraveling genetic variants and interactions contributing to comorbidity. | Wen Y et al. | β | 2013 | β |
| A complex interplay between personality domains, marital status and a variant in CHRNA5 on the risks of cocaine, nicotine dependences and cocaine-induced paranoia. | Zayats T et al. | β | 2013 | β |
| Cis-regulatory variants affect CHRNA5 mRNA expression in populations of African and European ancestry. | Wang JC et al. | β | 2013 | β |
| Molecular mechanisms underlying behaviors related to nicotine addiction. | Picciotto MR et al. | β | 2013 | β |
| Neuronal nicotinic acetylcholine receptors: common molecular substrates of nicotine and alcohol dependence. | Hendrickson LM et al. | β | 2013 | β |
| Nicotinic acetylcholine receptors: from basic science to therapeutics. | Hurst R et al. | β | 2013 | β |
| Nominal association with CHRNA4 variants and nicotine dependence. | Kamens HM et al. | β | 2013 | β |
| Profiling of childhood adversity-associated DNA methylation changes in alcoholic patients and healthy controls. | Zhang H et al. | β | 2013 | β |
| Role of Ξ±5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice. | Fowler CD et al. | β | 2013 | β |
| Variants in the 15q25 gene cluster are associated with risk for schizophrenia and bipolar disorder. | Jackson KJ et al. | β | 2013 | β |
| Candidate pathway association study in cocaine dependence: the control of neurotransmitter release. | FernΓ ndez-Castillo N et al. | β | 2012 | β |
| Development of novel pharmacotherapeutics for tobacco dependence: progress and future directions. | Harmey D et al. | β | 2012 | β |
| Externalizing behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster. | Stephens SH et al. | β | 2012 | β |
| From men to mice: CHRNA5/CHRNA3, smoking behavior and disease. | Ware JJ et al. | β | 2012 | β |
| Function of human Ξ±3Ξ²4Ξ±5 nicotinic acetylcholine receptors is reduced by the Ξ±5(D398N) variant. | George AA et al. | β | 2012 | β |
| Impact of human D398N single nucleotide polymorphism on intracellular calcium response mediated by Ξ±3Ξ²4Ξ±5 nicotinic acetylcholine receptors. | TammimΓ€ki A et al. | β | 2012 | β |
| Nicotine reward and affective nicotine withdrawal signs are attenuated in calcium/calmodulin-dependent protein kinase IV knockout mice. | Jackson KJ et al. | β | 2012 | β |
| Recent advances in the genetic epidemiology and molecular genetics of substance use disorders. | Kendler KS et al. | β | 2012 | β |
| The genetics of addiction-a translational perspective. | Agrawal A et al. | β | 2012 | β |
| The genetics of substance dependence. | Wang JC et al. | β | 2012 | β |
| Transgenic over expression of nicotinic receptor alpha 5, alpha 3, and beta 4 subunit genes reduces ethanol intake in mice. | Gallego X et al. | β | 2012 | β |
| A CHRNA5 allele related to nicotine addiction and schizophrenia. | Hong LE et al. | β | 2011 | β |
| A common genetic variant in the neurexin superfamily member CNTNAP2 is associated with increased risk for selective mutism and social anxiety-related traits. | Stein MB et al. | β | 2011 | β |
| Association of the CHRNA5-A3-B4 gene cluster with heaviness of smoking: a meta-analysis. | Ware JJ et al. | β | 2011 | β |
| Detecting genetic interactions for quantitative traits with U-statistics. | Li M et al. | β | 2011 | β |
| Genetic vulnerability and susceptibility to substance dependence. | Bierut LJ | β | 2011 | β |
| Markers in the 15q24 nicotinic receptor subunit gene cluster (CHRNA5-A3-B4) predict severity of nicotine addiction and response to smoking cessation therapy. | Sarginson JE et al. | β | 2011 | β |
| Nicotinic acetylcholine receptor-mediated mechanisms in lung cancer. | Improgo MR et al. | β | 2011 | β |
| Nicotinic Ξ±5 receptor subunit mRNA expression is associated with distant 5' upstream polymorphisms. | Smith RM et al. | β | 2011 | β |
| Recent advances in understanding nicotinic receptor signaling mechanisms that regulate drug self-administration behavior. | Tuesta LM et al. | β | 2011 | β |
| Single-nucleotide polymorphisms (5p15.33, 15q25.1, 6p22.1, 6q27 and 7p15.3) and lung cancer survival in the European Prospective Investigation into Cancer and Nutrition (EPIC). | Xun WW et al. | β | 2011 | β |
| The Role of the Habenula in Nicotine Addiction. | Baldwin PR et al. | β | 2011 | β |
| A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction. | Hong LE et al. | β | 2010 | β |
| ChIP-chip analysis of neurexins and other candidate genes for addiction and neuropsychiatric disorders. | Pedrosa E et al. | β | 2010 | β |
| Cigarette smoking and depression: a question of causation. | MunafΓ² MR et al. | β | 2010 | β |
| Convergence of genetic findings for nicotine dependence and smoking related diseases with chromosome 15q24-25. | Bierut LJ | β | 2010 | β |
| Genetics of addictions. | Hartz SM et al. | β | 2010 | β |
| Genetics of addictions. | Hartz SM et al. | β | 2010 | β |
| Incorporating age at onset of smoking into genetic models for nicotine dependence: evidence for interaction with multiple genes. | Grucza RA et al. | β | 2010 | β |
| Multiple cholinergic nicotinic receptor genes affect nicotine dependence risk in African and European Americans. | Saccone NL et al. | β | 2010 | β |
| Neuronal nicotinic acetylcholine receptors as pharmacotherapeutic targets for the treatment of alcohol use disorders. | Chatterjee S et al. | β | 2010 | β |
| Nicotinic acetylcholine receptor genes on chromosome 15q25.1 are associated with nicotine and opioid dependence severity. | Erlich PM et al. | β | 2010 | β |
| The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer. | Improgo MR et al. | β | 2010 | β |
| Variation in nicotinic acetylcholine receptor genes is associated with multiple substance dependence phenotypes. | Sherva R et al. | β | 2010 | β |
| Variation in the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 and its interaction with recent tobacco use influence cognitive flexibility. | Zhang H et al. | β | 2010 | β |
| Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions. | Greenbaum L et al. | β | 2009 | β |
| Long-lasting decreases in cocaine-reinforced behavior following treatment with the cholinesterase inhibitor tacrine in rats selectively bred for drug self-administration. | Grasing K et al. | β | 2009 | β |
| New insights into the genetics of addiction. | Li MD et al. | β | 2009 | β |
| Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery. | Lester HA et al. | β | 2009 | β |
| Smoking and smoking cessation in disadvantaged women: assessing genetic contributions. | Uhl GR et al. | β | 2009 | β |
| The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. | Saccone NL et al. | β | 2009 | β |
| Variants in nicotinic acetylcholine receptors alpha5 and alpha3 increase risks to nicotine dependence. | Chen X et al. | β | 2009 | β |
| Genetics of smoking behavior and its consequences: the role of nicotinic acetylcholine receptors. | Thorgeirsson TE et al. | β | 2008 | β |
| In search of causal variants: refining disease association signals using cross-population contrasts. | Saccone NL et al. | β | 2008 | β |
| Intermediacy and gene-environment interaction: the example of CHRNA5-A3 region, smoking, nicotine dependence, and lung cancer. | Wacholder S et al. | β | 2008 | β |
| Subtypes of nicotinic acetylcholine receptors in nicotine reward, dependence, and withdrawal: evidence from genetically modified mice. | Fowler CD et al. | β | 2008 | β |