Genome-wide association analyses suggested a novel mechanism for smoking behavior regulated by IL15.
- Authors
- Liu, Y-Z; Pei, Y-F; Guo, Y-F; Wang, L; Liu, X-G; Yan, H; Xiong, D-H; Zhang, Y-P; Levy, S; Li, J; Haddock, C K; Papasian, C J; Xu, Q; Ma, J Z; Payne, T J; Recker, R R; Li, M D; Deng, H-W
- Year
- 2009
- Journal
- Molecular psychiatry
- PMID
- 19188921
- DOI
- 10.1038/mp.2009.3
- PMCID
- PMC2700850
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 approximately 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 x 10(-8)) of genome-wide significance. Another SNP, rs17354547 that is highly conserved across multiple species achieved a P-value of 5.65 x 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.
Association signals for the 9 smoking behavior-associated SNPs detected upstream from the IL15 gene in male subjects in the GWASNote: The haplotype block map for the 9 SNPs was reconstructed using our own genotype data showing pairwise LD in r2.
Conservation of the SNP, rs17354547, and a potential transcription factor binding site containing this SNP, across multiple speciesNote: The sequence inside the box is a potential transcription factor binding site that may be modulated by the SNP rs17354547, according to FASTSNP analyses (21). The SNP and its flanking sequence are highly conserved across multiple species.
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