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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-02-03

AUTHORS

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

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. More... »

PAGES

668-680

Journal

TITLE

Molecular Psychiatry

ISSUE

7

VOLUME

14

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/mp.2009.3

DOI

http://dx.doi.org/10.1038/mp.2009.3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1018387846

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19188921


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