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      Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence

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          Abstract

          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.

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          Most cited references 58

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          Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1.

          To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 x 10(-17)) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.
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            A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.

            Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
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              Drugs of abuse: anatomy, pharmacology and function of reward pathways.

               George F Koob (1992)
              Drugs of abuse are very powerful reinforcers, and even in conditions of limited access (where the organism is not dependent) these drugs will motivate high rates of operant responding. This presumed hedonic property and the drugs' neuropharmacological specificity provide a means of studying the neuropharmacology and neuroanatomy of brain reward. Three major brain systems appear to be involved in drug reward--dopamine, opioid and GABA. Evidence suggests a midbrain-forebrain-extrapyramidal circuit with its focus in the nucleus accumbens. Data implicating dopamine and opioid systems in indirect sympathomimetic and opiate reward include critical elements in both the nucleus accumbens and ventral tegmental areas. Ethanol reward appears to depend on an interaction with the GABAA receptor complex but may also involve common elements such as dopamine and opioid peptides in this midbrain-forebrain-extrapyramidal circuit. These results suggest that brain reward systems have a multidetermined neuropharmacological basis that may involve some common neuroanatomical elements.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                October 2015
                06 October 2015
                1 October 2015
                : 5
                : 10
                : e651
                Affiliations
                [1 ]Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Research Division, Research Triangle Institute International , Research Triangle Park, NC, USA
                [2 ]deCODE Genetics/Amgen , Reykjavik, Iceland
                [3 ]Research Computing Division, Research Triangle Institute International , Research Triangle Park, NC, USA
                [4 ]Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University , Richmond, VA, USA
                [5 ]Nevada Institute of Personalized Medicine and Department of Psychology, University of Nevada , Las Vegas, NV, USA
                [6 ]Department of Genetics, Washington University in St. Louis , St. Louis, MO, USA
                [7 ]Department of Biostatistics and Informatics, University of Colorado Anschutz Medical Campus , Aurora, CO, USA
                [8 ]Department of Public Health, Faculty of Medicine, University of Helsinki , Helsinki, Finland
                [9 ]Department of Medicine (Biomedical Genetics), Boston University School of Medicine , Boston, MA, USA
                [10 ]Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute , National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, USA
                [11 ]Iowa Department of Public Health , Des Moines, IA, USA
                [12 ]Institute of Epidemiology I, German Research Center for Environmental Health , Neuherberg, Germany
                [13 ]Department of Genetic Epidemiology, University of Göttingen—Georg-August University Göttingen , Göttingen, Germany
                [14 ]Department of Psychiatry, Washington University School of Medicine , St. Louis, MO, USA
                [15 ]Department of Neurology, Boston University School of Medicine , Boston, MA, USA
                [16 ]Department of Ophthalmology, Boston University School of Medicine , Boston, MA, USA
                [17 ]Department of Genetics and Genomics, Boston University School of Medicine , Boston, MA, USA
                [18 ]Department of Epidemiology, Boston University School of Public Health , Boston, MA, USA
                [19 ]Department of Biostatistics, Boston University School of Public Health , Boston, MA, USA
                [20 ]National Institute for Health and Welfare , Helsinki, Finland
                [21 ]Institute for Molecular Medicine, University of Helsinki , Helsinki, Finland
                [22 ]Department of Psychiatry, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA, USA
                [23 ]VISN 4 Mental Illness Research, Education and Clinical Center, Philadelphia VA Medical Center , Philadelphia, PA, USA
                [24 ]Department of Psychiatry, Yale University School of Medicine , New Haven, CT, USA
                [25 ]Department of Genetics, Yale University School of Medicine , New Haven, CT, USA
                [26 ]Department of Neurobiology, Yale University School of Medicine , New Haven, CT, USA
                [27 ]VA CT Healthcare Center, Department of Psychiatry , West Haven, CT, USA
                [28 ]Center for Tobacco Research and Intervention, University of Wisconsin , Madison, WI, USA
                [29 ]Department of Epidemiology, Harvard University School of Public Health , Boston, MA, USA
                [30 ]Department of Biostatistics, Harvard University School of Public Health , Boston, MA, USA
                [31 ]Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth , Hanover, NH, USA
                [32 ]Department of Genetics, Geisel School of Medicine at Dartmouth , Hanover, NH, USA
                [33 ]Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth , Hanoven, NH, USA
                [34 ]Department of Epidemiology, University of Colorado Anschutz Medical Campus , Aurora, CO, USA
                [35 ]Fellow Program and Behavioral Health and Criminal Justice Research Division, Research Triangle Institute International , Research Triangle Park, NC, USA
                [36 ]Faculty of Medicine, University of Iceland , Reykjavik, Iceland
                Author notes
                [* ]Behavioral and Urban Health Program, Behavioral Health and Criminal Justice Research Division, Research Triangle Institute International , 3040 East Cornwallis Road, P.O. Box 12194, Research Triangle Park, NC 27709, USA. E-mail: dhancock@ 123456rti.org
                Article
                tp2015149
                10.1038/tp.2015.149
                4930126
                26440539
                Copyright © 2015 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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                Original Article

                Clinical Psychology & Psychiatry

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