Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Han, Haijun; Liu, Qiang; Yang, Zhongli; Wang, Mu; Ma, Yunlong; Cao, Liyu; Cui, Wenyan; Yuan, Wenji; Payne, Thomas; Li, Lanjuan; Li, Ming
• Is Part Of: Translational psychiatry. Volume 8:Issue 1(2018)
• Page Start: 1
• Page End: 10
• Publication Date: 2018-12
• Subjects: Psychiatry -- Research -- Periodicals; Neurosciences -- Research -- Periodicals; Psychiatry -- Periodicals; Neurosciences -- Periodicals; Translational Research -- Periodicals; Health Policy -- Periodicals; Public Health -- Periodicals; 616.89
• DOI: 10.1038/s41398-018-0290-8
• Languages: English
• ISSNs: 2158-3188

Abstract

Abstract Variants in serotonergic genes are implicated in nicotine dependence (ND) in subjects of European and African origin, but their involvement with smoking in Asians is largely unknown. Moreover, mechanisms underlying the ND risk-associated single-nucleotide polymorphisms (SNPs) in these genes are rarely investigated. The Fagerström Test for Nicotine Dependence (FTND) score was used to assess ND in 2616 male Chinese Han smokers. Both association and interaction analysis were used to examine the association of variants in the serotonergic genes with FTND. Further, expression and methylation quantitative trait loci (cis -mQTL) analysis was employed to determine the association of individual SNPs with the extent of methylation of each CpG locus. Individual SNP-based association analysis revealed that rs1176744 inHTR3B was marginally associated with FTND (p = 0.042). Haplotype-based association analysis found that one major haplotype, T-T-A-G, formed by SNPs rs3758987-rs4938056-rs1176744-rs2276305, located in the 5′ region ofHTR3B, showed a significant association with FTND (p = 0.00025). Further, a significant genetic interactive effect affecting ND was detected among SNPs rs10160548 inHTR3A, and rs3758987, rs2276305, and rs1672717 inHTR3B (p = 0.0074). Finally, we found four CpG sites (CpG_4543549, CpG_4543464, CpG_4543682, and CpG_4546888) to be significantly associated with threecis -mQTL SNPs (i.e., rs3758987, rs4938056, and rs1176744) located in our detected haplotype withinHTR3B . In sum, we showed SNP rs1176744 (Tyr129Ser) to be associated with ND. Together with the SNPs rs3758987 and rs4938056 inHTR3B, they formed a major haplotype, which had significant association with ND. We further showed these SNPs contribute to ND through four methylated sites inHTR3B . All these findings suggest that variants in the serotonergic system play an important role in ND in the Chinese Han population. More importantly, these findings demonstrated that the involvement of this system in ND is through gene-by-gene interaction and methylation.