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

Y. Z. Liu, Y. F. Pei, Y. F. Guo, L. Wang, X. G. Liu, H. Yan, D. H. Xiong, Y. P. Zhang, S. Levy, J. Li, C. K. Haddock, C. J. Papasian, Q. Xu, J. Z. Ma, T. J. Payne, R. R. Recker, M. D. Li, H. W. Deng

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37 Scopus citations

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 380000 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 × 108) of genome-wide significance. Another SNP, rs17354547 that is highly conserved across multiple species achieved a P-value of 5.65 × 105. 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

Original languageEnglish (US)
Pages (from-to)668-680
Number of pages13
JournalMolecular Psychiatry
Volume14
Issue number7
DOIs
StatePublished - Jul 2009

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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