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The contribution of rare and common variants in 30 genes to risk nicotine dependence

Molecular Psychiatry volume 20, pages 1467–1478 (2015)Cite this article

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Abstract

Genetic and functional studies have revealed that both common and rare variants of several nicotinic acetylcholine receptor subunits are associated with nicotine dependence (ND). In this study, we identified variants in 30 candidate genes including nicotinic receptors in 200 sib pairs selected from the Mid-South Tobacco Family population with equal numbers of African Americans (AAs) and European Americans (EAs). We selected 135 of the rare and common variants and genotyped them in the Mid-South Tobacco Case–Control (MSTCC) population, which consists of 3088 AAs and 1430 EAs. None of the genotyped common variants showed significant association with smoking status (smokers vs non-smokers), Fagerström Test for ND scores or indexed cigarettes per day after Bonferroni correction. Rare variants in NRXN1, CHRNA9, CHRNA2, NTRK2, GABBR2, GRIN3A, DNM1, NRXN2, NRXN3 and ARRB2 were significantly associated with smoking status in the MSTCC AA sample, with weighted sum statistic (WSS) P-values ranging from 2.42 × 10−3 to 1.31 × 10−4 after 106 phenotype rearrangements. We also observed a significant excess of rare nonsynonymous variants exclusive to EA smokers in NRXN1, CHRNA9, TAS2R38, GRIN3A, DBH, ANKK1/DRD2, NRXN3 and CDH13 with WSS P-values between 3.5 × 10−5 and 1 × 10−6. Variants rs142807401 (A432T) and rs139982841 (A452V) in CHRNA9 and variants V132L, V389L, rs34755188 (R480H) and rs75981117 (N549S) in GRIN3A are of particular interest because they are found in both the AA and EA samples. A significant aggregate contribution of rare and common coding variants in CHRNA9 to the risk for ND (SKAT-C: P=0.0012) was detected by applying the combined sum test in MSTCC EAs. Together, our results indicate that rare variants alone or combined with common variants in a subset of 30 biological candidate genes contribute substantially to the risk of ND.

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Acknowledgements

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.

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  1. J Yang and S Wang: These authors contributed equally to this work.

Authors and Affiliations

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

    J Yang, S Wang, Z Yang & M D Li

  2. Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, MD, USA

    C A Hodgkinson, P Iarikova & D Goldman

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

    J Z Ma

  4. Department of Otolaryngology and Communicative Sciences, ACT Center for Tobacco Treatment, Education and Research, University of Mississippi Medical Center, Jackson, MS, USA

    T J Payne

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Yang, J., Wang, S., Yang, Z. et al. The contribution of rare and common variants in 30 genes to risk nicotine dependence. Mol Psychiatry 20, 1467–1478 (2015). https://doi.org/10.1038/mp.2014.156

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