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Transl Psychiatry. 2015 Oct 6;5:e651. doi: 10.1038/tp.2015.149.

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

Author information

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.

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.

PMID:
26440539
PMCID:
PMC4930126
DOI:
10.1038/tp.2015.149
[Indexed for MEDLINE]
Free PMC Article

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