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Significant associations of CHRNA2 and CHRNA6 with nicotine dependence in European American and African American populations

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Abstract

The direct physiological effects that promote nicotine dependence (ND) are mediated by nicotinic acetylcholine receptors (nAChRs). In line with the genetic and pharmacological basis of addiction, many previous studies have revealed significant associations between variants in the nAChR subunit genes and various measures of ND in different ethnic samples. In this study, we first examined the association of variants in nAChR subunits α2 (CHRNA2) and α6 (CHRNA6) genes on chromosome 8 with ND using a family sample consisting of 1,730 European Americans (EAs) from 495 families and 1,892 African Americans (AAs) from 424 families (defined as the discovery family sample). ND was assessed by two standard quantitative measures: smoking quantity (SQ) and the Fagerström Test for ND (FTND). We found nominal associations for all seven tested SNPs of the genes with at least one ND measure in the EA sample and for two SNPs in CHRNA2 in the AA sample. Of these, associations of SNPs rs3735757 with FTND (P = 0.0068) and rs2472553 with both ND measures (with a P value of 0.0043 and 0.00086 for SQ and FTND, respectively) continued to be significant in the EA sample even after correction for multiple tests. Further, we found several haplotypes that were significantly associated with ND in the EA sample in CHRNA6 and in the both EA and AA samples in CHRNA2. To confirm the associations of the two genes with ND, we conducted a replication study with an independent case–control sample from the SAGE study, which showed a significant association of the two genes with ND, although the significantly associated SNPs were not always the same in the two samples. Together, these findings indicate that both CHRNA2 and CHRNA6 play a significant role in the etiology of ND in AA and EA smokers. Further replication in additional independent samples is warranted.

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Acknowledgments

We acknowledge the invaluable contributions of personal information and blood samples by all participants in the study. This project was supported by National Institutes of Health grant R01 DA012844 to MDL. We are thankful to the NIH GWAS data repository for providing us access to their dataset through project 771 to Ming D. Li under the title “Genome-wide association analysis for addiction and type 2 diabetes.” We also thank NIH GWAS Data Repository, the investigators who contributed the phenotype and genotype data from original studies, and the primary funding organization that supported the contributing study. Funding support for SAGE was provided through the NIH Genes, Environment and Health Initiative (GEI) Grant U01 HG004422; the GENEVA Coordinating Center (U01 HG004446); the National Institute on Alcohol Abuse and Alcoholism (U10 AA008401); the National Institute on Drug Abuse (R01 DA013423); the National Cancer Institute (P01 CA089392); and the NIH contract “High throughput genotyping for studying the genetic contributions to human disease” (HHSN268200782096C). Assistance with data cleansing was provided by the National Center for Biotechnology Information. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research or at deCODE. Funding support for the GWAS of Lung Cancer and Smoking was provided through the NIH Genes, Environment and Health 7 Initiative [GEI] (Z01 CP 010200). The human subjects participating in the GWAS derive from The Environment and Genetics in Lung Cancer Etiology (EAGLE) case–control study and the Prostate, Lung Colon and Ovary Screening Trial, and these studies were supported by intramural resources of the National Cancer Institute. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies, GENEVA Coordinating Center (U01HG004446). Assistance with data cleansing was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000093.

Conflict of interest

MDL has served as a consultant and board member of ADial Pharmaceuticals, LLC. All other authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Psychiatry and Neurobehavioral Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USA

    Shaolin Wang, Andrew D van der Vaart, Qing Xu, Chamindi Seneviratne & Ming D. Li

  2. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    Ovide F. Pomerleau & Cynthia S. Pomerleau

  3. ACT Center for Tobacco Treatment, Education and Research and Department of Otolaryngology, University of Mississippi Medical Center, Jackson, USA

    Thomas J. Payne

  4. Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA

    Jennie Z. Ma

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  1. Shaolin Wang
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Correspondence to Ming D. Li.

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Wang, S., D van der Vaart, A., Xu, Q. et al. Significant associations of CHRNA2 and CHRNA6 with nicotine dependence in European American and African American populations. Hum Genet 133, 575–586 (2014). https://doi.org/10.1007/s00439-013-1398-9

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