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Genome-wide association analyses suggested a novel mechanism for smoking behavior regulated by IL15

Molecular Psychiatry volume 14, pages 668–680 (2009)Cite this article

Abstract

Cigarette smoking is the leading preventable cause of death in the United States. Although smoking behavior has a significant genetic determination, the specific genes and associated mechanisms underlying the smoking behavior are largely unknown. Here, we carried out a genome-wide association study on smoking behavior in 840 Caucasians, including 417 males and 423 females, in which we examined ∼380 000 single nucleotide polymorphisms (SNPs). We found that a cluster of nine SNPs upstream from the IL15 gene were associated with smoking status in males, with the most significant SNP, rs4956302, achieving a P-value (8.80 × 10−8) of genome-wide significance. Another SNP, rs17354547 that is highly conserved across multiple species achieved a P-value of 5.65 × 10−5. These two SNPs, together with two additional SNPs (rs1402812 and rs4956396) were selected from the above nine SNPs for replication in an African-American sample containing 1251 subjects, including 412 males and 839 females. The SNP rs17354547 was replicated successfully in the male subgroup of the replication sample; it was associated with smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerstrom Test for Nicotine Dependence (FTND), with P-values of 0.031, 0.0046 and 0.019, respectively. In addition, a haplotype formed by rs17354547, rs1402812 and rs4956396 was also associated with SQ, HSI and FTND, achieving P-values of 0.039, 0.0093 and 0.0093, respectively. To further confirm our findings, we carried out an in silico replication study of the nine SNPs in a Framingham Heart Study sample containing 7623 Caucasians from 1731 families, among which, 3491 subjects were males and 4132 were females. Again, the male-specific association with smoking status was observed, for which seven of the nine SNPs achieved significant P-values (P<0.05) and two achieved marginally significant P-values (P<0.10) in males. Several of the nine SNPs, including the highly conserved one across species, rs17354547, are located at potential transcription factor binding sites, suggesting transcription regulation as a possible function for these SNPs. Through this function, the SNPs may modulate the gene expression of IL15, a key cytokine regulating immune function. As the immune system has long been recognized to influence drug addiction behavior, our association findings suggest a novel mechanism for smoking addiction involving immune modulation through the IL15 pathway.

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Acknowledgements

Investigators of this work were supported partially by Grants from NIH (R01 AR050496-01, R21 AG027110, R01 AG026564, R21 AA015973, P50 AR055081 and R01 DA12844). This study also benefited from grants from National Science Foundation of China, Huo Ying Dong Education Foundation, HuNan Province, Xi’an Jiaotong University and the Ministry of Education of China. The Framingham Heart Study and the Framingham SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University. The Framingham SHARe data used for the analyses described in this paper were obtained through dbGaP (accession number phs000007.v3.p2). This paper was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or the NHLBI.

Author information

Authors and Affiliations

  1. School of Medicine, University of Missouri – Kansas City, Kansas City, MO, USA

    Y-Z Liu, Y-F Pei, Y-F Guo, L Wang, X-G Liu, H Yan, Y-P Zhang, J Li, C K Haddock, C J Papasian & H-W Deng

  2. The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, PR China

    Y-F Pei, Y-F Guo, L Wang, X-G Liu, H Yan, Y-P Zhang & H-W Deng

  3. Osteoporosis Research Center, Creighton University, Omaha, NE, USA

    D-H Xiong & R R Recker

  4. Vanderbilt Microarray Shared Resource, Vanderbilt University, Nashville, TN, USA

    S Levy

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

    Q Xu & M D Li

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

    J Z Ma

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

    T J Payne

  8. Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, PR, China

    H-W Deng

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  1. Y-Z Liu
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  10. J Li
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Corresponding author

Correspondence to H-W Deng.

Appendices

Appendix I

The most significant 30 single nucleotide polymorphisms (SNPs) for the association with smoking status identified in the current genome-wide association studies (GWAS) Table A1

Table 5 Table a1
Full size table

Appendix II

Genotype distribution at the nine single nucleotide plymorphisms (SNPs) upstream of the IL15 gene Table A2

Table 6 Table a2
Full size table

Appendix III

Results of analyses of potential sample stratification

Appendix IV

Quantile-quantile plots for the P-values achieved in the genome-wide association studies (GWAS)

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Liu, YZ., Pei, YF., Guo, YF. et al. Genome-wide association analyses suggested a novel mechanism for smoking behavior regulated by IL15. Mol Psychiatry 14, 668–680 (2009). https://doi.org/10.1038/mp.2009.3

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