Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.
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- Authors
- Hancock, D B; Reginsson, G W; Gaddis, N C; Chen, X; Saccone, N L; Lutz, S M; Qaiser, B; Sherva, R; Steinberg, S; Zink, F; Stacey, S N; Glasheen, C; Chen, J; Gu, F; Frederiksen, B N; Loukola, A; Gudbjartsson, D F; Brüske, I; Landi, M T; Bickeböller, H; Madden, P; Farrer, L; Kaprio, J; Kranzler, H R; Gelernter, J; Baker, T B; Kraft, P; Amos, C I; Caporaso, N E; Hokanson, J E; Bierut, L J; Thorgeirsson, T E; Johnson, E O; Stefansson, K
- Year
- 2015
- Journal
- Translational psychiatry
- PMID
- 26440539
- DOI
- 10.1038/tp.2015.149
- PMCID
- PMC4930126
We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.
SNP and indel associations with nicotine dependence from meta-analyses of discovery and independent replication samples, all of European-ancestry. The −log10 (meta-analysis P) results are plotted by chromosomal position: (a) genome-wide meta-analysis results across the five discovery samples (total N=17 074) for 9.9 million genotyped and imputed SNPs and indels tested for association with nicotine dependence (SNPs shown as circles and indels shown as triangles) with minor allele frequency >0.01 and (b) regional meta-analysis results across all 10 discovery and replication samples (total N=24 543) in the CHRNA4 gene on chromosome 20q13. For the regional plot, the r2 values between the top SNP (rs2273500, shown in purple) and other SNPs in the flanking region were based on the 1000 Genomes European reference panel (denoted EUR); the indels are shown in gray. The solid black lines mark the genome-wide statistical significance threshold (meta-analysis P<5 × 10−8). indel, insertion/deletion; SNP, single nucleotide polymorphism.
Association of the rs2273500 minor allele (C) with severe vs mild nicotine dependence across all the samples. rs2273500 had the lowest P-value for its association with nicotine dependence in meta-analysis across all the samples, which are sorted by their size. Black-filled diamonds indicate the discovery samples, and open diamonds indicate the replication samples. The odds ratio (OR) estimates are shown proportional to the sample size. CI, confidence interval; COGEND, Collaborative Genetic Study of Nicotine Dependence; COPDGene, Chronic Obstructive Pulmonary Disease Gene Study; EAGLE, Environment and Genetics in Lung Cancer Etiology Study; FTC, Finnish Twin Cohort Study; GAIN, Genetic Association Information Network GWAS of schizophrenia; nonGAIN, Molecular Genetics of Schizophrenia—nonGAIN sample; SAGE*, Study of Addiction: Genetics and Environment (*indicates that overlapping COGEND participants were excluded); UW-TTURC, University of Wisconsin-Transdisciplinary Tobacco Use Research Center.
Associations of the top nicotine dependence-associated SNP rs2273500 with transcript-level and exon-level CHRNA4 mRNA expression in intralobular white matter from 134 European-ancestry participants in the UK Brain Expression Consortium. The probe size (in base pairs) is indicated, and P-values <0.05 are shown in bold. SNP, single nucleotide polymorphism.
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In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Addiction Susceptibility: Genetic Factors, Personality Traits, and Epigenetic Interactions with the Gut Microbiome. | Borrego-Ruiz A et al. | — | 2025 | → |
| Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review. | Jalaiei A et al. | — | 2025 | → |
| Reduced risk of schizophrenia among first-degree relatives of individuals with lung Cancer: A nationwide longitudinal study. | Chen JP et al. | — | 2025 | → |
| Nicotine Motivated Behavior in <i>C. elegans</i>. | Salim C et al. | — | 2024 | → |
| Deciphering gene contributions and etiologies of somatic mutational signatures of cancer. | Ji X et al. | — | 2023 | → |
| Hepatocyte CHRNA4 mediates the MASH-promotive effects of immune cell-produced acetylcholine and smoking exposure in mice and humans. | Pan C et al. | — | 2023 | → |
| Rare coding variants in CHRNB2 reduce the likelihood of smoking. | Rajagopal VM et al. | — | 2023 | → |
| The collaborative study on the genetics of alcoholism: Genetics. | Johnson EC et al. | — | 2023 | → |
| A polygenic approach to the association between smoking and schizophrenia. | Al-Soufi L et al. | — | 2022 | → |
| A Systematic Review of Genetic Polymorphisms Associated with Bipolar Disorder Comorbid to Substance Abuse. | de Marco A et al. | — | 2022 | → |
| Common and distinguishing genetic factors for substance use behavior and disorder: an integrated analysis of genomic and transcriptomic studies from both human and animal studies. | Chang XW et al. | — | 2022 | → |
| Genetic insights into smoking behaviours in 10,558 men of African ancestry from continental Africa and the UK. | Piga NN et al. | — | 2022 | → |
| Clarifying the Genetic Influences on Nicotine Dependence and Quantity of Use in Cigarette Smokers. | Verhulst B et al. | — | 2021 | → |
| Genetics of substance use disorders: a review. | Deak JD et al. | — | 2021 | → |
| Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers. | Lesseur C et al. | — | 2021 | → |
| Genome-Wide Gene-by-Smoking Interaction Study of Chronic Obstructive Pulmonary Disease. | Kim W et al. | — | 2021 | → |
| Identifying risk factors involved in the common versus specific liabilities to substance use: A genetically informed approach. | Iob E et al. | — | 2021 | → |
| Impact of a Medical Diagnosis on Decision to Stop Smoking and Successful Smoking Cessation. | Lindsay HG et al. | — | 2021 | → |
| Little Evidence of Modified Genetic Effect of rs16969968 on Heavy Smoking Based on Age of Onset of Smoking. | Adjangba C et al. | — | 2021 | → |
| Methylome and transcriptome signature of bronchoalveolar cells from multiple sclerosis patients in relation to smoking. | Ringh MV et al. | — | 2021 | → |
| Revision of the Wisconsin Smoking Withdrawal Scale: Development of brief and long forms. | Smith SS et al. | — | 2021 | → |
| An update on the role of common genetic variation underlying substance use disorders. | Johnson EC et al. | — | 2020 | → |
| Assessing the Role of Long Noncoding RNA in Nucleus Accumbens in Subjects With Alcohol Dependence. | Drake J et al. | — | 2020 | → |
| Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits. | Quach BC et al. | — | 2020 | → |
| Genetic feedback for psychiatric conditions: Where are we now and where are we going. | Driver MN et al. | — | 2020 | → |
| Genetics of Smoking Behaviors in American Indians. | Henderson JA et al. | — | 2020 | → |
| Genome-Wide Association Study of Smoking Behavior Traits in a Chinese Han Population. | Li M et al. | — | 2020 | → |
| Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes. | Chen J et al. | — | 2020 | → |
| Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci. | Erzurumluoglu AM et al. | — | 2020 | → |
| Prediction of Smoking Behavior From Single Nucleotide Polymorphisms With Machine Learning Approaches. | Xu Y et al. | — | 2020 | → |
| Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis. | Datta U et al. | — | 2020 | → |
| Translational Molecular Approaches in Substance Abuse Research. | Fulton SL et al. | — | 2020 | → |
| A decade in psychiatric GWAS research. | Horwitz T et al. | — | 2019 | → |
| Common and Rare Variants Genetic Association Analysis of Cigarettes per Day Among Ever-Smokers in Chronic Obstructive Pulmonary Disease Cases and Controls. | Lutz SM et al. | — | 2019 | → |
| Genetic Advances in Chronic Obstructive Pulmonary Disease. Insights from COPDGene. | Ragland MF et al. | — | 2019 | → |
| Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans. | Wetherill L et al. | — | 2019 | → |
| Genome-Wide Variants Shared Between Smoking Quantity and Schizophrenia on 15q25 Are Associated With CHRNA5 Expression in the Brain. | Ohi K et al. | — | 2019 | → |
| Smoking Rates and Number of Cigarettes Smoked per Day in Schizophrenia: A Large Cohort Meta-Analysis in a Japanese Population. | Ohi K et al. | — | 2019 | → |
| The relationship between nicotine and psychosis. | Quigley H et al. | — | 2019 | → |
| A hierarchical clustering method for dimension reduction in joint analysis of multiple phenotypes. | Liang X et al. | — | 2018 | → |
| Biochemical, demographic, and self-reported tobacco-related predictors of the acute heart rate response to nicotine in smokers. | Jensen KP et al. | — | 2018 | → |
| From genes to treatments: a systematic review of the pharmacogenetics in smoking cessation. | Salloum NC et al. | — | 2018 | → |
| Genetic correlation between smoking behaviors and schizophrenia. | Hartz SM et al. | — | 2018 | → |
| Genetic variation in CHRNA7 and CHRFAM7A is associated with nicotine dependence and response to varenicline treatment. | Cameli C et al. | — | 2018 | → |
| Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence. | Hancock DB et al. | — | 2018 | → |
| Genome-Wide Association Study of Heavy Smoking and Daily/Nondaily Smoking in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). | Saccone NL et al. | — | 2018 | → |
| Human Genetics of Addiction: New Insights and Future Directions. | Hancock DB et al. | — | 2018 | → |
| Pathways to precision medicine in smoking cessation treatments. | Chen LS et al. | — | 2018 | → |
| Post-GWAS in Psychiatric Genetics: A Developmental Perspective on the "Other" Next Steps. | Dick DM et al. | — | 2018 | → |
| The Value of Biosamples in Smoking Cessation Trials: A Review of Genetic, Metabolomic, and Epigenetic Findings. | Saccone NL et al. | — | 2018 | → |
| A general approach to testing for pleiotropy with rare and common variants. | Lutz SM et al. | — | 2017 | → |
| A Novel Tobacco Use Phenotype Suggests the 15q25 and 19q13 Loci May be Differentially Associated With Cigarettes per Day and Tobacco-Related Problems. | Richmond-Rakerd LS et al. | — | 2017 | → |
| Genetics of addictive behavior: the example of nicotine dependence. | Gorwood P et al. | — | 2017 | → |
| Genome-wide association study implicates<i>CHRNA2</i>in cannabis use disorder | Demontis D et al. | — | 2017 | — |
| Genome-wide meta-analysis identifies a novel susceptibility signal at CACNA2D3 for nicotine dependence. | Yin X et al. | — | 2017 | → |
| Neuropeptide systems and new treatments for nicotine addiction. | Bruijnzeel AW | — | 2017 | → |
| Pharmacogenetic study of seven polymorphisms in three nicotinic acetylcholine receptor subunits in smoking-cessation therapies. | Pintarelli G et al. | — | 2017 | → |
| The genetic epidemiology of substance use disorder: A review. | Prom-Wormley EC et al. | — | 2017 | → |
| A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants. | Bacchelli E et al. | — | 2016 | → |
| A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences. | Thorgeirsson TE et al. | — | 2016 | → |
| A threshold model for opposing actions of acetylcholine on reward behavior: Molecular mechanisms and implications for treatment of substance abuse disorders. | Grasing K | — | 2016 | → |
| Genome-Wide Association of the Laboratory-Based Nicotine Metabolite Ratio in Three Ancestries. | Baurley JW et al. | — | 2016 | → |
| Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population. | Zanetti KA et al. | — | 2016 | → |
| Genome-wide single nucleotide polymorphism heritability of nicotine dependence as a multidimensional phenotype. | Bidwell LC et al. | — | 2016 | → |
| Hemizygous Deletion on Chromosome 3p26.1 Is Associated with Heavy Smoking among African American Subjects in the COPDGene Study. | Begum F et al. | — | 2016 | → |
| How Intravenous Nicotine Administration in Smokers Can Inform Tobacco Regulatory Science. | Jensen KP et al. | — | 2016 | → |
| Meta-Analyses of Genome-Wide Association Data Hold New Promise for Addiction Genetics. | Agrawal A et al. | — | 2016 | → |
| Neurobiology of addiction: a neurocircuitry analysis. | Koob GF et al. | — | 2016 | → |
| Rapporteur summaries of plenary, symposia, and oral sessions from the XXIIIrd World Congress of Psychiatric Genetics Meeting in Toronto, Canada, 16-20 October 2015. | Zai G et al. | — | 2016 | → |
| Replicated Risk Nicotinic Cholinergic Receptor Genes for Nicotine Dependence. | Zuo L et al. | — | 2016 | → |
| Smokescreen: a targeted genotyping array for addiction research. | Baurley JW et al. | — | 2016 | → |