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Mol Psychiatry. 2016 May;21(5):601-7. doi: 10.1038/mp.2015.105. Epub 2015 Aug 4.

Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.

Author information

1
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
2
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
3
Behavioral Health Epidemiology program, RTI International, Research Triangle Park, NC, USA.
4
Department of Medicine and Division of Biostatistics, Washington University School of Medicine, St Louis, MO, USA.
5
Center for Inherited Disease Research, Johns Hopkins University, Baltimore, MD, USA.
6
Department of Biostatistics, University of Washington, Seattle, WA, USA.
7
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
8
Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
9
Departments of Medicine and Epidemiology, Columbia University Medical Center, New York, NY, USA.
10
Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA.
11
Department of Neurosciences, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
12
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
13
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
14
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
15
Harvard Medical School, Boston, MA, USA.
16
University of Mississippi Medical Center, Jackson, MS, USA.
17
Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
18
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
19
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
20
Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA, USA.
21
Group Health Research Institute, Group Health, Seattle, WA, USA.
22
Division of Biostatistics, Washington University School of Medicine in St. Louis, St Louis, MO, USA.
23
Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA, USA.
24
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
25
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
26
Jackson State University, School of Public Service, Jackson, MS, USA.
27
Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.
28
Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.
29
Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.

Abstract

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

PMID:
26239294
PMCID:
PMC4740321
DOI:
10.1038/mp.2015.105
[Indexed for MEDLINE]
Free PMC Article

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