The  CHRNA5–A3–B4  Gene Cluster and Smoking: From Discovery to Therapeutics

Lassi, Glenda; Taylor, Amy E; Timpson, Nicholas J.; Kenny, Paul J.; Mather, Robert J.; Eisen, Timothy; Munafò, Marcus R

doi:10.1016/j.tins.2016.10.005

Cited by 70 publications

(62 citation statements)

References 56 publications

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“…To conclude, the present study provides multiple-level, yet preliminary evidence that, in people at high-risk for severe smoking outcomes, gene variants from the nicotinic pathway may further moderate the risk for specific tobacco smoking phenotypes. Associations showed both a polygenic and a pleiotropic nature that included SNP x SNP interactions, in line with previous research in less specific populations [14]. Taken altogether, our findings also highlight the importance of metabolic and chaperone/trafficking proteins in the pathogenicity of nAChRs.…”

Section: Discussionsupporting

confidence: 91%

“…The present study replicated the previously identified associations between CHRNA3 and smoking behaviours, including the number of CPD, which typically involved rs1051730 [14], a plausible tag marker for functional haplotypes in the CHRNA5-A3-B4 cluster. This makes rs8040868 a relatively new SNP of interest in the cluster.…”

Section: Discussionsupporting

confidence: 89%

“…Finally, pleiotropy, i.e. simultaneous associations between a given gene or SNP with several smoking phenotypes is expected [14], as in most complex traits [15].…”

Section: Introductionmentioning

confidence: 99%

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Gene-Gene interactions and pleiotropy in the brain nicotinic pathway associated with the heaviness and precocity of tobacco smoking among outpatients with multiple substance use disorders

Icick

Besson

Zerdazi

et al. 2019

Preprint

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Introduction: Tobacco smoking is a major health burden worldwide, especially in populations suffering from other substance use disorders (SUDs). Several smoking phenotypes have been associated with single nucleotide polymorphisms (SNPs) of nicotinic acetylcholine receptors (nAChRs). Yet, little is known about the genetics of tobacco smoking in populations with other SUDs, particularly regarding gene-gene interactions and pleiotropy, which are likely involved in the polygenic architecture of SUDs. Thus, we undertook a candidate pathway association study of nAChR-related genes and smoking phenotypes in a sample of SUD patients.Methods: 493 patients with genetically-verified Caucasian ancestry were characterized extensively regarding patterns of tobacco smoking, other SUDs, and 83 SNPs from the nicotinic pathway, encompassing all brain nAChR subunits and metabolic/chaperone/trafficking proteins. Single-SNP, gene-based and SNP x SNP interactions analyses were performed to investigate associations with relevant tobacco smoking phenotypes. This included Bayesian analyses to detect pleiotropy, and adjustment on clinical and sociodemographic confounders. Results:After multiple adjustment, we found independent associations between CHRNA3 rs8040868 and a higher number of cigarettes per day (CPD), and between RIC3 rs11826236 and a lower age at smoking initiation. Two SNP x SNP interactions were associated with age at onset (AAO) of daily smoking. There was pleiotropy regarding three SNPs in CHRNA3 (CPD, AAO daily smoking), ACHE (CPD, HSI) and CHRNB4 (CPD, both AAOs). Discussion:Despite limitations, the present study shows that the genetics of tobacco smoking in SUD patients are both distinct and partially shared across smoking phenotypes, and involve metabolic and chaperone effectors of the nicotinic pathway.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

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Gene-Gene interactions and pleiotropy in the brain nicotinic pathway associated with the heaviness and precocity of tobacco smoking among outpatients with multiple substance use disorders

Icick

Besson

Zerdazi

et al. 2019

Preprint

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“…A recent survey by counted a total of 287 human genetics studies on nicotine dependence, including 242 candidate gene association, 22 genome-wide linkage, 18 GWAS, and five targeted sequencing studies. We refer readers to existing reviews for detailed findings (Greenbaum & Lerer, 2009;Wang & Li, 2009;Lassi et al, 2016;Wen et al, 2016). In brief, several neurotransmitter systems, such as the acetylcholinergic, dopaminergic, GABAergic, and glutamatergic systems, have been implicated.…”

Section: Human Genetic Studiesmentioning

confidence: 99%

Neurogenetic determinants and mechanisms of addiction to nicotine and smoked tobacco

Sharp

Chen

2018

Eur J of Neuroscience

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The single most preventable cause of disease, disability, and death in the United States is tobacco use. Decades of study show that the risk of becoming addicted to smoked cigarettes varies greatly amongst individuals and is heritable, yet environmental factors are also important contributors. In this review, we consider a wide range of methodologies and key published reports that have defined the inheritance of different stages of nicotine‐dependent smoking behavior, including preference, initiation, regular use, withdrawal and dependence as well as cessation and relapse. Major findings from both animal and human studies are discussed. Current findings converge primarily on the role of nicotinic cholinergic receptor subunits, although other neurotransmitter systems as well as nicotine metabolism enzymes are implicated. Various stages of nicotine addiction may share common genetic mechanisms, yet several lines of evidence indicate that each stage also has its own unique genetic determinants. Studies on the heritability of smoking initiation demonstrate substantial evidence for gene–environment interaction, although the precise molecular genetic mechanism(s) remains unknown. Considering the relatively few genes identified so far and the small to modest fraction of the variance in risk for a particular smoking phenotype (e.g., smoking initiation in late adolescence) attributable to these genes, a large gap remains to be filled in order to account for the heritability of key phenotypes involved in each stage of addiction to smoked tobacco. Looking forward, new research strategies involving both human and animal studies will produce the fundamental genetic insights that are the foundation for the precision medical treatment of individuals addicted to smoked tobacco.

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“…The vMHb/IP pathway is also of interest due to its expression of unusual acetylcholine receptor subunits, including the channel‐forming α3 and β4 receptor subunits in the vMHb, and the “accessory” α5 receptor subunit expressed in the IP subnuclei that receive vMHb input (Hsu et al, ; Marks et al, ; Salas et al, ). These nicotinic receptors are of special interest because the genes encoding the α5/α3/β4 subunits are colocated in the mouse and human genomes, and in humans, alleles at this locus, including a functional variant in the α5 receptor, have been associated with smoking behavior (Berrettini & Doyle, ; Lassi et al, ).…”

Section: Introductionmentioning

confidence: 99%

Specific connections of the interpeduncular subnuclei reveal distinct components of the habenulopeduncular pathway

Quina¹,

Harris

Zeng

et al. 2017

J of Comparative Neurology

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The habenulopeduncular pathway consists of the medial habenula (MHb), its output tract, the fasciculus retroflexus, and its principal target, the interpeduncular nucleus (IP). Several IP subnuclei have been described, but their specific projections and relationship to habenula inputs are not well understood. Here we have used viral, transgenic, and conventional anterograde and retrograde tract-tracing methods to better define the relationship between the dorsal and ventral MHb, the IP, and the secondary efferent targets of this system. Although prior studies have reported that the IP has ascending projections to ventral forebrain structures, we find that these projections originate almost entirely in the apical subnucleus, which may be more appropriately described as part of the median raphe system. The laterodorsal tegmental nucleus receives inhibitory inputs from the contralateral dorsolateral IP, and mainly excitatory inputs from the ipsilateral rostrolateral IP subnucleus. The midline central gray of the pons and nucleus incertus receive input from the rostral IP, which contains a mix of inhibitory and excitatory neurons, and the dorsomedial IP, which is exclusively inhibitory. The lateral central gray of the pons receives bilateral input from the lateral IP, which in turn receives bilateral input from the dorsal MHb. Taken together with prior studies of IP projections to the raphe, these results form an emerging map of the habenulopeduncular system that has significant implications for the proposed function of the IP in a variety of behaviors, including models of mood disorders and behavioral responses to nicotine.

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The CHRNA5–A3–B4 Gene Cluster and Smoking: From Discovery to Therapeutics

Cited by 70 publications

References 56 publications

Gene-Gene interactions and pleiotropy in the brain nicotinic pathway associated with the heaviness and precocity of tobacco smoking among outpatients with multiple substance use disorders

Gene-Gene interactions and pleiotropy in the brain nicotinic pathway associated with the heaviness and precocity of tobacco smoking among outpatients with multiple substance use disorders

Neurogenetic determinants and mechanisms of addiction to nicotine and smoked tobacco

Specific connections of the interpeduncular subnuclei reveal distinct components of the habenulopeduncular pathway

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