Affinage

CHRNA5

Neuronal acetylcholine receptor subunit alpha-5 · UniProt P30532

Length
468 aa
Mass
53.1 kDa
Annotated
2026-04-28
100 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHRNA5 encodes the α5 accessory subunit of neuronal nicotinic acetylcholine receptors (nAChRs), which assembles into heteropentameric (α4β2)2α5-type channels to govern the kinetics, desensitization, and calcium permeability of cholinergic signaling across brain circuits and peripheral tissues. In prefrontal cortex layer VI corticothalamic neurons, α5 is required for rapid-onset postsynaptic cholinergic excitation and protection against desensitization during sustained acetylcholine release, and its loss slows cholinergic kinetics and alters developmental dendritic morphology (PMID:32817066, PMID:24055499); in the habenulo-interpeduncular pathway, α5-containing receptors on GABAergic neurons mediate nicotine aversion, and the common D398N risk variant (rs16969968) reduces receptor calcium permeability and IPN neuronal responsiveness, thereby attenuating aversion and promoting heavier nicotine and alcohol consumption (PMID:29954848, PMID:30293722, PMID:25948103, PMID:21968931). CHRNA5 expression is controlled by cis-regulatory haplotypes and DNA methylation quantitative trait loci operating across multiple brain regions and lung tissue (PMID:20733116, PMID:24303001, PMID:26220977), and in peripheral epithelia, α5 acts as a negative regulator of cell motility and invasion through calcium-dependent and MAPK/ERK signaling, with loss or silencing enhancing proliferation and migration in bronchial, lung cancer, and head-and-neck cancer cells (PMID:21586512, PMID:39472448).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    Determining the genomic architecture of the CHRNA5/A3/B4 cluster—including a partial tail-to-tail overlap between CHRNA5 and CHRNA3—established the structural framework needed to interpret cis-regulatory effects at this locus.

    Evidence Genomic cloning and intron-exon structure determination of the human locus

    PMID:11721883

    Open questions at the time
    • No functional consequence of the CHRNA5-CHRNA3 overlap was tested
    • Regulatory elements not mapped
  2. 2010 High

    Identifying that promoter haplotypes drive differential CHRNA5 mRNA levels in lung tissue and that ASCL1 directly regulates the cluster in small-cell lung carcinoma provided the first transcriptional control mechanisms for CHRNA5 expression.

    Evidence Luciferase reporter assays in lung cancer lines plus RT-PCR in 68 patient lung samples; ASCL1 siRNA knockdown in SCLC cells

    PMID:20124469 PMID:20733116

    Open questions at the time
    • Chromatin-level validation of ASCL1 binding (e.g. ChIP) not performed
    • Tissue-specificity of promoter haplotype effects beyond lung not tested
  3. 2011 High

    Demonstrating that α5 loss-of-function in bronchial and cancer cells increases motility, invasion, and calcium influx in a CHRNA7-dependent manner established CHRNA5 as a negative regulator of nicotinic pro-migratory signaling in peripheral epithelia, while BAC transgenic mice showed that overexpression of the cluster enhances habenular activation and nicotine self-administration in vivo.

    Evidence siRNA knockdown and α-conotoxin MII inhibition in bronchial/cancer cells with motility and calcium assays; BAC transgenic mouse with receptor binding, self-administration, and neuroimaging

    PMID:21586512 PMID:22101982

    Open questions at the time
    • Specific α5-containing receptor stoichiometry mediating the peripheral anti-migratory effect not defined
    • Transgenic overexpression cannot distinguish contributions of α5 vs. α3 vs. β4 subunits
  4. 2013 High

    Allele-specific expression analysis in human frontal cortex across two ancestral populations proved that cis-regulatory variants in a 9 kb region directly control CHRNA5 transcript levels in the brain, while knockout mouse studies demonstrated that α5 determines the lasting teratogenic effects of developmental nicotine on prefrontal layer VI neuron morphology and nAChR currents.

    Evidence Allele-specific expression in 160 post-mortem brains; Chrna5 KO vs. WT mice with developmental nicotine, electrophysiology, and morphological analysis

    PMID:24055499 PMID:24303001

    Open questions at the time
    • Specific causal variant within the 9 kb cis-regulatory region not pinpointed
    • Behavioral attention consequences of the developmental morphological changes not directly measured
  5. 2015 High

    Linking nicotine dependence-associated SNPs to CHRNA5 DNA methylation and mRNA expression across multiple brain regions established an epigenetic regulatory layer connecting genetic risk to receptor expression.

    Evidence Cis-meQTL analysis in post-mortem brain (two cohorts, n=240), correlated with mRNA and nicotine dependence in five independent cohorts

    PMID:26220977

    Open questions at the time
    • Causal directionality (methylation → expression vs. expression → methylation) not experimentally resolved
    • No manipulation of methylation to confirm functional consequence
  6. 2017 High

    The D398N risk variant (rs16969968) was shown to decrease calcium permeability and increase desensitization of (α4β2)2α5 receptors in vitro, and in human smokers the risk allele specifically reduced aversive responses to intravenous nicotine while improving cognitive control, directly linking receptor biophysics to the behavioral mechanism of heavy smoking.

    Evidence In vitro electrophysiology of heterologously expressed receptors; controlled IV nicotine challenge in 192 genotyped smokers

    PMID:21968931 PMID:25948103

    Open questions at the time
    • In vitro biophysical data reported within a review rather than primary research article
    • No structural model explaining how D398N alters pore calcium permeability
  7. 2018 High

    Circuit-level studies in knockout mice and humanized knock-in rats demonstrated that α5-containing receptors in GABAergic IPN neurons are essential for nicotine-evoked electrophysiological responses and that the D398N variant reduces IPN activity to increase nicotine self-administration and reinstatement, establishing the habenula-IPN axis as the critical circuit for α5-mediated nicotine aversion.

    Evidence Chrna5-KO and Chrna5-Cre mice with electrophysiology and optogenetics in IPN; α5SNP knock-in rats with self-administration, reinstatement, c-Fos, and electrophysiology

    PMID:29954848 PMID:30293722

    Open questions at the time
    • Downstream signaling from IPN GABAergic projections to raphe/tegmentum not functionally dissected
    • Whether the D398N variant also affects non-IPN circuits contributing to aversion is unknown
  8. 2019 High

    Extending the D398N variant's behavioral impact beyond nicotine, humanized knock-in rats showed increased alcohol consumption and relapse to both alcohol and food seeking, with altered insular cortex activation, demonstrating a general role for α5 in reward-related behavior.

    Evidence α5SNP knock-in rats with voluntary alcohol consumption, reinstatement paradigms, and c-Fos in insula

    PMID:31288250

    Open questions at the time
    • Mechanism by which α5 in the insula regulates alcohol/food reward not delineated
    • Whether IPN or insula is the primary site mediating the alcohol phenotype is unresolved
  9. 2020 High

    Optogenetic release of endogenous acetylcholine onto prefrontal layer VI neurons showed that α5 is specifically required for rapid-onset cholinergic excitation and resistance to desensitization, and that the α-α site agonist NS9283 can pharmacologically rescue these kinetics, identifying a potential therapeutic approach.

    Evidence Chrna5-KO × ChAT-ChR2 mice, whole-cell patch clamp in PFC slices, NS9283 pharmacological rescue

    PMID:32817066

    Open questions at the time
    • Whether NS9283 rescues attention deficits in vivo in α5-KO mice not tested
    • Receptor stoichiometry on layer VI neurons not directly measured
  10. 2023 High

    Single-cell transcriptomics revealed that Chrna5-expressing cortical neurons include acetylcholine 'super-responders' with subplate identity expressing lynx prototoxin family genes (Lypd1, Ly6g6e, Lypd6b) that modulate their nicotinic responses, uncovering a cell-type-specific regulatory layer for α5 receptor function.

    Evidence Chrna5-Cre transgenic mice, opto-physiological recordings, single-cell RNA-seq, pharmacological manipulation

    PMID:36798433

    Open questions at the time
    • Whether lynx family members directly bind α5-containing receptors or act indirectly is unknown
    • Functional consequences of lynx modulation on attention behavior not assessed
  11. 2024 Medium

    In cancer cells, CHRNA5 was linked to pro-tumorigenic signaling through the MEK/ERK pathway with CES1 identified as a physical interaction partner, expanding the downstream signaling repertoire beyond calcium and into oncogenic kinase cascades.

    Evidence Co-immunoprecipitation, molecular docking, siRNA/overexpression, transcriptomics, and nude mouse xenograft in HNSCC

    PMID:39472448

    Open questions at the time
    • CES1 interaction awaits reciprocal validation and confirmation in non-cancer cells
    • Whether CES1 interaction is direct or mediated through the assembled receptor pentamer is unresolved
    • Relationship between CHRNA5's anti-migratory role in bronchial cells and pro-tumorigenic role in HNSCC not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis by which the D398N substitution alters receptor pore properties, the identity of the causal cis-regulatory variant(s) controlling brain CHRNA5 expression, and the mechanism distinguishing CHRNA5's anti-migratory function in normal epithelia from its pro-tumorigenic roles in certain cancers remain unresolved.
  • No cryo-EM or crystal structure of the (α4β2)2α5 receptor with D398N
  • Causal variant fine-mapping within the 9 kb cis-regulatory region not completed
  • Context-dependent oncogenic vs. tumor-suppressive function of CHRNA5 not mechanistically explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005634 nucleus 1
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 3
Partners
ASCL1CES1CHRNA3CHRNA4CHRNA7CHRNB2CHRNB4
Complex memberships
(α4β2)2α5 nicotinic acetylcholine receptorα3β4α5 nicotinic acetylcholine receptor

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 CHRNA5 acts as a negative regulator of nicotine signaling in bronchial cells: siRNA-mediated silencing of CHRNA5 or pharmacological inhibition with α-conotoxin MII increased cell motility, invasiveness, and calcium influx in a nicotine-like manner; effects on motility were blocked by inhibiting CHRNA7, and silencing decreased expression of cell adhesion molecules P120 and ZO-1, as well as DeltaNp63α in squamous cell carcinoma lines. RNA interference (siRNA knockdown), pharmacological inhibition (α-conotoxin MII), in vitro motility/invasion assays, calcium influx measurement, immunofluorescence Carcinogenesis High 21586512
2010 ASCL1 transcription factor directly regulates expression of the CHRNA5/A3/B4 gene cluster in small-cell lung carcinoma (SCLC): knockdown of ASCL1 in SCLC cells significantly decreased CHRNA5, CHRNA3, and CHRNB4 expression without affecting other nAChR genes, and in silico analysis revealed ASCL1 binding sites in all three promoters. siRNA knockdown of ASCL1, quantitative RT-PCR, in silico promoter analysis Molecular cancer research : MCR Medium 20124469
2010 Promoter haplotypes of CHRNA5 regulate its mRNA expression levels in lung tissue: three 5' promoter haplotypes were significantly associated with differential CHRNA5 transcript levels in non-tumor lung parenchyma, and luciferase reporter assays confirmed that these haplotypes drive differential promoter activity in lung cancer cell lines. Real-time PCR quantification of transcript levels in 68 patient lung samples, luciferase reporter assays in A549/H460/H520/H596 cell lines Journal of the National Cancer Institute High 20733116
2011 CHRNA5 promoter variants affect relative expression: deletion at rs3841324 combined with variation at rs503464 decreased CHRNA5 promoter-driven luciferase activity in BE(2)-C cells, potentially due to loss of an SP-1 binding site; 5'UTR variants rs55853698 and rs55781567 also altered luciferase expression; a distal promoter region strongly repressed CHRNA5 transcription. Luciferase reporter assays, allelic expression imbalance (AEI) in post-mortem brain tissue, heterologous promoter constructs PloS one Medium 21858091
2013 Cis-regulatory variants in a 9 kb region of the CHRNA5-CHRNA3-CHRNB4 cluster exert direct cis-regulatory effects on CHRNA5 transcript levels in human frontal cortex of both African and European ancestry, as demonstrated by quantitative allele-specific expression analysis. Quantitative allele-specific gene expression in post-mortem frontal cortex (49 African ancestry + 111 European ancestry subjects) PloS one High 24303001
2011 Overexpression of the human CHRNA5/A3/B4 genomic cluster in transgenic mice increased functional α3β4-nAChRs in relevant brain regions, increased sensitivity to nicotine's pharmacological effects, increased activation of the medial habenula, reduced activation of dopaminergic neurons in the VTA after acute nicotine, and increased acquisition of nicotine self-administration. BAC transgenic mouse overexpressing human CHRNA5/A3/B4 cluster; receptor binding assays, pharmacological challenge, nicotine self-administration, in vivo neuroimaging Amino acids High 22101982
2018 In the interpeduncular nucleus (IPN), electrophysiological responses to nicotinic acetylcholine receptor stimulation are markedly reduced in α5 (Chrna5)-null mice; Chrna5-expressing IPN neurons are GABAergic and project to mesopontine raphe and tegmentum; optogenetic stimulation of Chrna5-expressing IPN neurons becomes aversive after priming by prior stimulation or nicotine exposure, supporting a role for α5 in mediating nicotine aversion. Chrna5 knockout mice, electrophysiology, BAC recombineering to generate Chrna5-Cre transgenic mice, optogenetics, reporter expression, immunohistochemistry The Journal of neuroscience High 29954848
2018 Transgenic rats expressing the human CHRNA5 risk variant (rs16969968/α5SNP, D398N) self-administered more nicotine at high doses and exhibited higher nicotine-induced reinstatement of nicotine seeking than wild-type rats; this was associated with altered IPN neuronal activity (c-Fos), and IPN neurons of α5SNP rats showed reduced electrophysiological response to nicotine. Zinc finger nuclease knock-in rats, intravenous nicotine self-administration, reinstatement paradigm, c-Fos immunostaining, electrophysiology Current biology : CB High 30293722
2016 iPSC-derived human dopaminergic and glutamatergic neurons homozygous for the N398 risk allele of CHRNA5 (rs16969968) showed increased excitatory postsynaptic current response upon nicotine application compared to D398 neurons, with rapid desensitization; N398 DA neurons also differentially expressed genes associated with ligand receptor interaction and synaptic function. iPSC derivation from human donors, neuronal differentiation, whole-cell electrophysiology, gene expression profiling Scientific reports High 27698409
2017 The CHRNA5 risk allele (rs16969968*A) was associated with lower ratings of aversive effects of intravenous nicotine in human smokers with marked specificity, and with greater improvement on a measure of cognitive control (Stroop Task) following nicotine administration, supporting reduced nicotine aversion as the mechanism by which this variant promotes heavy smoking. Human IV nicotine challenge study (n=192), genotyped at rs16969968; subjective ratings, cardiovascular reactivity, cognitive task performance Neuropsychopharmacology High 25948103
2013 In mouse prefrontal layer VI corticothalamic neurons, developmental in vivo nicotine exposure modified apical dendrite morphology and nAChR currents in a direction dependent on Chrna5 genotype: in wildtype mice nicotine produced immature morphology and reduced nAChR currents persisting into adulthood, whereas in α5-knockout mice nicotine normalized these parameters, demonstrating that Chrna5 determines the long-lasting teratogenic effects of developmental nicotine on prefrontal attention circuitry. Wildtype vs. Chrna5 knockout mice, in vivo developmental nicotine exposure, patch-clamp electrophysiology, morphological analysis of layer VI neurons Neuropharmacology High 24055499
2020 Chrna5 in prefrontal cortex layer VI neurons is critical for the rapid onset of postsynaptic cholinergic responses: loss of α5 slows cholinergic excitation and delays its peak following optogenetic release of endogenous acetylcholine; α5 also protects nicotinic responses against desensitization during sustained stimulation; the α-α nicotinic binding site agonist NS9283 restored rapid-onset kinetics without triggering desensitization. Chrna5 knockout mice crossed with ChAT-ChR2 optogenetic mice, whole-cell electrophysiology in prefrontal cortex slices, pharmacological rescue with NS9283 The Journal of neuroscience High 32817066
2023 Chrna5-expressing neurons in prefrontal cortex include a distinct population of acetylcholine 'super-responders' with subplate identity, expressing a unique complement of GPI-anchored lynx prototoxin genes (Lypd1, Ly6g6e, Lypd6b) that regulate their nicotinic receptor responses; pharmacological manipulation of the lynx-regulated pathway modulated endogenous cholinergic activation. Chrna5-Cre transgenic mice, opto-physiological experiments, single-cell transcriptomics, pharmacological manipulation iScience High 36798433
2015 SNPs associated with nicotine dependence in the CHRNA5 region are also associated with CHRNA5 DNA methylation in multiple human brain regions (prefrontal cortex, frontal cortex, temporal cortex, pons); specifically, the rs11636753 major allele (G) was associated with lower CHRNA5 DNA methylation, lower CHRNA5 mRNA expression, and increased nicotine dependence risk, linking epigenetic regulation to functional mRNA levels. Cis-methylation QTL analysis in post-mortem brain (BrainCloud and Brain QTL cohorts, n=240 total), mRNA expression correlation, nicotine dependence association in 5 independent cohorts Human molecular genetics High 26220977
2016 The CHRNA5 enhancer haplotype tagged by rs880395 increases CHRNA5 mRNA expression across all tissues and also enhances expression of a CHRNA5 antisense RNA (RP11-650L12.2) and CHRNA3, suggesting DNA looping to multiple promoters; in nucleus accumbens and putamen specifically, CHRNA3 expression associates with a distinct haplotype tagged by rs1948 in the CHRNB4 3'UTR. Integration of GTEx RNA expression data (brain and peripheral tissues), linkage disequilibrium analysis, haplotype/diplotype analysis with GWAS data Human mutation Medium 27758088
2019 Transgenic rats expressing the human CHRNA5 risk variant (α5SNP) consumed more alcohol and exhibited increased relapse to alcohol seeking after abstinence, associated with altered activity in the insula (c-Fos); relapse to food seeking was also increased, demonstrating a general role for this polymorphism in reward processing beyond nicotine. α5SNP knock-in rats, voluntary alcohol consumption, reinstatement paradigm, c-Fos immunostaining, food-seeking relapse paradigm Neuropsychopharmacology High 31288250
2012 Chrna5 knockout in mice reduced the severity of imiquimod-induced psoriasis and regulated inflammation through the MAPK kinase kinase-1/JNK-MAPK/NF-κB pathway; single-cell sequencing revealed reduced keratinocyte subpopulations and downregulated JAK/STAT signaling after Chrna5 knockout; silencing CHRNA5 in human keratinocytes inhibited proliferation and migration. Chrna5 knockout mice, imiquimod psoriasis model, single-cell sequencing, siRNA knockdown in human keratinocytes, pathway analysis The Journal of investigative dermatology Medium 35513071
2018 Chrna5 variant (D398N/rs16969968) interacts with developmental nicotine exposure to alter nicotine intake in offspring: D398N (N allele) pups exposed to nicotine in utero consumed the most nicotine at the highest concentration, while D allele pups exposed to nicotine consumed the least; this correlated with opposing effects on nicotine-stimulated dopamine release from striatal synaptosomes. Knock-in mice expressing the human D398N SNP, 2-bottle choice nicotine intake, striatal synaptosome dopamine release assay Genes, brain, and behavior Medium 29573323
2024 In head and neck squamous cell carcinoma (HNSCC) cells, CHRNA5 knockdown reduced proliferation, migration, and invasion; nicotine exposure upregulated CHRNA5 and reversed these effects; transcriptomics linked CHRNA5 to the MEK/ERK pathway; co-immunoprecipitation identified CES1 as a CHRNA5-interacting protein; CHRNA5 knockdown reduced p-MEK, p-ERK, and CES1 levels, and nicotine reversed these changes; in vivo xenograft data confirmed the pathway. siRNA knockdown and overexpression, CCK-8 proliferation assay, wound healing and Transwell invasion assays, co-immunoprecipitation, molecular docking, western blot, transcriptomics, nude mouse xenograft Cell death & disease Medium 39472448
2022 In hepatocellular carcinoma (HCC), CHRNA5 regulates YAP activity to control proliferation; CHRNA5 also promotes stemness through Nanog, Sox2, and OCT4, and promotes EMT-associated metastasis; in vivo assays confirmed CHRNA5's role in tumor growth. CHRNA5 knockdown and overexpression in HCC cell lines, in vitro proliferation/migration/invasion assays, stemness assays, in vivo tumor formation in mice, western blot Pharmaceutics Medium 35214008
2023 In lung cancer cells, nicotine downregulates JWA expression via the CHRNA5-mediated AKT pathway; lower JWA enhanced CD44 expression through inhibition of SP1 ubiquitination-mediated degradation; thus CHRNA5 activation by nicotine drives cancer cell stemness and progression via a CHRNA5→AKT→JWA→SP1→CD44 axis. siRNA and overexpression constructs, GSEA, western blot, in vivo xenograft, JAC4 inhibitor treatment Ecotoxicology and environmental safety Medium 37224781
2001 Genomic characterization of the CHRNA5/A3/B4 cluster revealed the intron-exon structure of CHRNA5 and CHRNB4, and identified two previously unknown introns within the 3'UTR of CHRNA3 causing a partial tail-to-tail overlap with CHRNA5, establishing the genomic architecture of this locus. Sequence analysis, genomic cloning, intron-exon structure determination Journal of human genetics High 11721883
2017 The nonsynonymous CHRNA5 variant rs16969968 (D398N) confers decreased calcium permeability and more extensive desensitization of (α4β2)2α5-type nicotinic receptors in in vitro cellular studies, raising the possibility that a positive allosteric modulator might have therapeutic potential. In vitro cellular functional studies (cited within review) Molecular psychiatry Medium 21968931

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The CHRNA5-CHRNA3-CHRNB4 nicotinic receptor subunit gene cluster affects risk for nicotine dependence in African-Americans and in European-Americans. Cancer research 218 19706762
2008 A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction. PLoS genetics 216 18618000
2008 The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer. Journal of the National Cancer Institute 184 18957677
2008 Genetic variation in the CHRNA5 gene affects mRNA levels and is associated with risk for alcohol dependence. Molecular psychiatry 180 18414406
2011 Relationship between CYP2A6 and CHRNA5-CHRNA3-CHRNB4 variation and smoking behaviors and lung cancer risk. Journal of the National Cancer Institute 152 21747048
2012 Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. American journal of respiratory and critical care medicine 147 22837378
2007 The CHRNA5/A3/B4 gene cluster variability as an important determinant of early alcohol and tobacco initiation in young adults. Biological psychiatry 146 18163978
2009 A common genetic variant in the 15q24 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) is associated with a reduced ability of women to quit smoking in pregnancy. Human molecular genetics 121 19429911
2008 Association of a single nucleotide polymorphism in neuronal acetylcholine receptor subunit alpha 5 (CHRNA5) with smoking status and with 'pleasurable buzz' during early experimentation with smoking. Addiction (Abingdon, England) 118 18783506
2008 A risk allele for nicotine dependence in CHRNA5 is a protective allele for cocaine dependence. Biological psychiatry 117 18519132
2012 Interplay of genetic risk factors (CHRNA5-CHRNA3-CHRNB4) and cessation treatments in smoking cessation success. The American journal of psychiatry 115 22648373
2011 Genetic variation at CHRNA5-CHRNA3-CHRNB4 interacts with smoking status to influence body mass index. International journal of epidemiology 94 21593077
2011 Association of the CHRNA5-A3-B4 gene cluster with heaviness of smoking: a meta-analysis. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 94 22071378
2009 Association of serum cotinine level with a cluster of three nicotinic acetylcholine receptor genes (CHRNA3/CHRNA5/CHRNB4) on chromosome 15. Human molecular genetics 91 19628476
2012 Higher FKBP5, COMT, CHRNA5, and CRHR1 allele burdens are associated with PTSD and interact with trauma exposure: implications for neuropsychiatric research and treatment. Neuropsychiatric disease and treatment 79 22536069
2011 Markers in the 15q24 nicotinic receptor subunit gene cluster (CHRNA5-A3-B4) predict severity of nicotine addiction and response to smoking cessation therapy. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 74 21268243
2011 The CHRNA5-A3-B4 gene cluster in nicotine addiction. Molecular psychiatry 70 21968931
2010 The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer. Progress in neurobiology 70 20685379
2010 Associations of variants in CHRNA5/A3/B4 gene cluster with smoking behaviors in a Korean population. PloS one 70 20808433
2015 A CHRNA5 Smoking Risk Variant Decreases the Aversive Effects of Nicotine in Humans. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 67 25948103
2010 Mediating effects of smoking and chronic obstructive pulmonary disease on the relation between the CHRNA5-A3 genetic locus and lung cancer risk. Cancer 63 20564069
2015 CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis. Journal of the National Cancer Institute 62 25873736
2010 TTC12-ANKK1-DRD2 and CHRNA5-CHRNA3-CHRNB4 influence different pathways leading to smoking behavior from adolescence to mid-adulthood. Biological psychiatry 62 21168125
2016 The CHRNA5-A3-B4 Gene Cluster and Smoking: From Discovery to Therapeutics. Trends in neurosciences 60 27871728
2012 Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4) interacts with maternal self-reported smoking status during pregnancy to influence birth weight. Human molecular genetics 58 22956269
2011 A CHRNA5 allele related to nicotine addiction and schizophrenia. Genes, brain, and behavior 55 21418140
2012 From men to mice: CHRNA5/CHRNA3, smoking behavior and disease. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 54 22544838
2010 Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 52 20886544
2010 Association and interaction analysis of variants in CHRNA5/CHRNA3/CHRNB4 gene cluster with nicotine dependence in African and European Americans. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 51 19859904
2012 Analysis of detailed phenotype profiles reveals CHRNA5-CHRNA3-CHRNB4 gene cluster association with several nicotine dependence traits. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 50 22241830
2014 Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers. PLoS genetics 49 25474695
2014 Contribution of Variants in CHRNA5/A3/B4 Gene Cluster on Chromosome 15 to Tobacco Smoking: From Genetic Association to Mechanism. Molecular neurobiology 47 25471942
2010 From smoking to lung cancer: the CHRNA5/A3/B4 connection. Oncogene 45 20581870
2011 CHRNA5 as negative regulator of nicotine signaling in normal and cancer bronchial cells: effects on motility, migration and p63 expression. Carcinogenesis 43 21586512
2018 Relationship of common variants in CHRNA5 with early-onset schizophrenia and executive function. Schizophrenia research 40 30366711
2011 Association between CHRNA5 genetic variation at rs16969968 and brain reactivity to smoking images in nicotine dependent women. Drug and alcohol dependence 40 21764527
2018 Chrna5-Expressing Neurons in the Interpeduncular Nucleus Mediate Aversion Primed by Prior Stimulation or Nicotine Exposure. The Journal of neuroscience : the official journal of the Society for Neuroscience 38 29954848
2018 A Human Polymorphism in CHRNA5 Is Linked to Relapse to Nicotine Seeking in Transgenic Rats. Current biology : CB 36 30293722
2010 Promoter polymorphisms and transcript levels of nicotinic receptor CHRNA5. Journal of the National Cancer Institute 36 20733116
2016 Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-Analysis. EBioMedicine 35 27543155
2015 Lack of Associations of CHRNA5-A3-B4 Genetic Variants with Smoking Cessation Treatment Outcomes in Caucasian Smokers despite Associations with Baseline Smoking. PloS one 34 26010901
2016 Increased nicotine response in iPSC-derived human neurons carrying the CHRNA5 N398 allele. Scientific reports 31 27698409
2015 Genetic variation (CHRNA5), medication (combination nicotine replacement therapy vs. varenicline), and smoking cessation. Drug and alcohol dependence 30 26142345
2015 Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. Molecular psychiatry 30 26239294
2013 Distinct loci in the CHRNA5/CHRNA3/CHRNB4 gene cluster are associated with onset of regular smoking. Genetic epidemiology 29 24186853
2011 Overexpression of the CHRNA5/A3/B4 genomic cluster in mice increases the sensitivity to nicotine and modifies its reinforcing effects. Amino acids 29 22101982
2010 ASCL1 regulates the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. Molecular cancer research : MCR 28 20124469
2019 Low Smoking Exposure, the Adolescent Brain, and the Modulating Role of CHRNA5 Polymorphisms. Biological psychiatry. Cognitive neuroscience and neuroimaging 26 31072760
2015 A multiancestry study identifies novel genetic associations with CHRNA5 methylation in human brain and risk of nicotine dependence. Human molecular genetics 25 26220977
2010 Variation in the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 and its interaction with recent tobacco use influence cognitive flexibility. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 25 20631687
2001 Characterization of the genomic structure of the human neuronal nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster and identification of novel intragenic polymorphisms. Journal of human genetics 25 11721883
2016 The CHRNA5/CHRNA3/CHRNB4 Nicotinic Receptor Regulome: Genomic Architecture, Regulatory Variants, and Clinical Associations. Human mutation 24 27758088
2015 Gene variance in the nicotinic receptor cluster (CHRNA5-CHRNA3-CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers. Journal of internal medicine 24 26689306
2011 Chromosome 15q25 (CHRNA3-CHRNA5) variation impacts indirectly on lung cancer risk. PloS one 24 21559498
2013 Chrna5 genotype determines the long-lasting effects of developmental in vivo nicotine exposure on prefrontal attention circuitry. Neuropharmacology 23 24055499
2020 Genetic Variant in CHRNA5 and Response to Varenicline and Combination Nicotine Replacement in a Randomized Placebo-Controlled Trial. Clinical pharmacology and therapeutics 22 32602170
2019 Genome-Wide Variants Shared Between Smoking Quantity and Schizophrenia on 15q25 Are Associated With CHRNA5 Expression in the Brain. Schizophrenia bulletin 22 30202994
2014 DRD2/CHRNA5 interaction on prefrontal biology and physiology during working memory. PloS one 22 24819610
2013 Scrutiny of the CHRNA5-CHRNA3-CHRNB4 smoking behavior locus reveals a novel association with alcohol use in a Finnish population based study. International journal of molecular epidemiology and genetics 22 23875064
2011 Externalizing behaviors are associated with SNPs in the CHRNA5/CHRNA3/CHRNB4 gene cluster. Behavior genetics 22 22042234
2019 Profound alteration in reward processing due to a human polymorphism in CHRNA5: a role in alcohol dependence and feeding behavior. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 21 31288250
2012 The CHRNA5/A3/B4 gene cluster and tobacco, alcohol, cannabis, inhalants and other substance use initiation: replication and new findings using mixture analyses. Behavior genetics 21 22382757
2020 Genetic susceptibility to nicotine addiction: Advances and shortcomings in our understanding of the CHRNA5/A3/B4 gene cluster contribution. Neuropharmacology 20 32738310
2012 Method for evaluating multiple mediators: mediating effects of smoking and COPD on the association between the CHRNA5-A3 variant and lung cancer risk. PloS one 20 23077662
2024 Nicotine-induced CHRNA5 activation modulates CES1 expression, impacting head and neck squamous cell carcinoma recurrence and metastasis via MEK/ERK pathway. Cell death & disease 19 39472448
2020 Chrna5 is Essential for a Rapid and Protected Response to Optogenetic Release of Endogenous Acetylcholine in Prefrontal Cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 19 32817066
2012 Association of nicotine dependence susceptibility gene, CHRNA5, with Parkinson's disease age at onset: gene and smoking status interaction. Parkinsonism & related disorders 19 22884254
2011 Association of the nicotine metabolite ratio and CHRNA5/CHRNA3 polymorphisms with smoking rate among treatment-seeking smokers. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 19 21385908
2011 Single nucleotide polymorphisms in CHRNA5 rs16969968, CHRNA3 rs578776, and LOC123688 rs8034191 are associated with heaviness of smoking in women in Northeastern Ontario, Canada. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 19 21810735
2011 In vitro and ex vivo analysis of CHRNA3 and CHRNA5 haplotype expression. PloS one 19 21858091
2013 Cis-regulatory variants affect CHRNA5 mRNA expression in populations of African and European ancestry. PloS one 18 24303001
2012 Polymorphisms of CHRNA5-CHRNA3-CHRNB4 Gene Cluster and NSCLC Risk in Chinese Population. Translational oncology 17 23397474
2011 A twin association study of nicotine dependence with markers in the CHRNA3 and CHRNA5 genes. Behavior genetics 17 21748402
2023 Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons. iScience 16 36798433
2022 CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity. Pharmaceutics 16 35214008
2014 Interplay of genetic risk (CHRNA5) and environmental risk (partner smoking) on cigarette smoking reduction. Drug and alcohol dependence 16 25073833
2016 SNPs in NRXN1 and CHRNA5 are associated to smoking and regulation of GABAergic and glutamatergic pathways. Pharmacogenomics 15 27355804
2015 CHRNA5 polymorphisms and risk of lung cancer in Chinese Han smokers. American journal of cancer research 15 26693074
2013 CHRNA5-A3-B4 genetic variants alter nicotine intake and interact with tobacco use to influence body weight in Alaska Native tobacco users. Addiction (Abingdon, England) 15 23692359
2023 JWA inhibits nicotine-induced lung cancer stemness and progression through CHRNA5/AKT-mediated JWA/SP1/CD44 axis. Ecotoxicology and environmental safety 14 37224781
2018 Cholinergic Receptor Nicotinic Alpha 5 (CHRNA5) RNAi is associated with cell cycle inhibition, apoptosis, DNA damage response and drug sensitivity in breast cancer. PloS one 14 30543688
2014 CHRNA5 variant predicts smoking cessation in patients with acute myocardial infarction. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 14 24727484
2013 Examination of rare missense variants in the CHRNA5-A3-B4 gene cluster to level of response to alcohol in the San Diego Sibling Pair study. Alcoholism, clinical and experimental research 14 23458267
2013 Genomics and personalized medicine: CHRNA5-CHRNA3-CHRNB4 and smoking cessation treatment. Journal of food and drug analysis 14 25214750
2010 Low ethanol concentration alters CHRNA5 RNA levels during early human development. Reproductive toxicology (Elmsford, N.Y.) 14 20438829
2018 Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence. BMC genomics 13 30453884
2013 Association of CHRNA5-A3-B4 variation with esophageal squamous cell carcinoma risk and smoking behaviors in a Chinese population. PloS one 13 23844051
2011 Association of a variant in the CHRNA5-A3-B4 gene cluster region to heavy smoking in the Italian population. European journal of human genetics : EJHG 13 21248747
2022 CHRNA5 Is Overexpressed in Patients with Psoriasis and Promotes Psoriasis-Like Inflammation in Mouse Models. The Journal of investigative dermatology 11 35513071
2020 Association of CHRNA5 Gene Variants with Crack Cocaine Addiction. Neuromolecular medicine 11 32152934
2018 The interaction of the Chrna5 D398N variant with developmental nicotine exposure. Genes, brain, and behavior 11 29573323
2014 A recall-by-genotype study of CHRNA5-A3-B4 genotype, cotinine and smoking topography: study protocol. BMC medical genetics 11 24451018
2014 CHRNA5 and CHRNA3 variants and level of neuroticism in young adult Mexican American men and women. Twin research and human genetics : the official journal of the International Society for Twin Studies 11 24588897
2013 Smoking status, snus use, and variation at the CHRNA5-CHRNA3-CHRNB4 locus in relation to obesity: the GLACIER study. American journal of epidemiology 11 23729684
2012 Nicotine dependence and comorbid psychiatric disorders: examination of specific genetic variants in the CHRNA5-A3-B4 nicotinic receptor genes. Drug and alcohol dependence 11 22336398
2012 Functional effect of polymorphisms in 15q25 locus on CHRNA5 mRNA, bulky DNA adducts and TP53 mutations. International journal of cancer 11 23011884
2021 The Cumulative Effect of Gene-Gene Interactions Between GSTM1, CHRNA3, CHRNA5 and SOD3 Gene Polymorphisms Combined with Smoking on COPD Risk. International journal of chronic obstructive pulmonary disease 10 34707353
2016 IREB2, CHRNA5, CHRNA3, FAM13A & hedgehog interacting protein genes polymorphisms & risk of chronic obstructive pulmonary disease in Tatar population from Russia. The Indian journal of medical research 10 28474623
2014 Identification of CHRNA5 rare variants in African-American heavy smokers. Psychiatric genetics 10 24682045
2012 The polymorphism of the CHRNA5 gene and the strength of nicotine addiction in lung cancer and COPD patients. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) 10 21955800