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Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers
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 rare...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221882/ https://www.ncbi.nlm.nih.gov/pubmed/30405098 http://dx.doi.org/10.1038/s41398-018-0290-8 |
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author | Han, Haijun Liu, Qiang Yang, Zhongli Wang, Mu Ma, Yunlong Cao, Liyu Cui, Wenyan Yuan, Wenji Payne, Thomas J. Li, Lanjuan Li, Ming D. |
author_facet | Han, Haijun Liu, Qiang Yang, Zhongli Wang, Mu Ma, Yunlong Cao, Liyu Cui, Wenyan Yuan, Wenji Payne, Thomas J. Li, Lanjuan Li, Ming D. |
author_sort | Han, Haijun |
collection | PubMed |
description | 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 in HTR3B 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 of HTR3B, showed a significant association with FTND (p = 0.00025). Further, a significant genetic interactive effect affecting ND was detected among SNPs rs10160548 in HTR3A, and rs3758987, rs2276305, and rs1672717 in HTR3B (p = 0.0074). Finally, we found four CpG sites (CpG_4543549, CpG_4543464, CpG_4543682, and CpG_4546888) to be significantly associated with three cis-mQTL SNPs (i.e., rs3758987, rs4938056, and rs1176744) located in our detected haplotype within HTR3B. In sum, we showed SNP rs1176744 (Tyr129Ser) to be associated with ND. Together with the SNPs rs3758987 and rs4938056 in HTR3B, they formed a major haplotype, which had significant association with ND. We further showed these SNPs contribute to ND through four methylated sites in HTR3B. 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. |
format | Online Article Text |
id | pubmed-6221882 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62218822018-11-09 Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers Han, Haijun Liu, Qiang Yang, Zhongli Wang, Mu Ma, Yunlong Cao, Liyu Cui, Wenyan Yuan, Wenji Payne, Thomas J. Li, Lanjuan Li, Ming D. Transl Psychiatry Article 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 in HTR3B 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 of HTR3B, showed a significant association with FTND (p = 0.00025). Further, a significant genetic interactive effect affecting ND was detected among SNPs rs10160548 in HTR3A, and rs3758987, rs2276305, and rs1672717 in HTR3B (p = 0.0074). Finally, we found four CpG sites (CpG_4543549, CpG_4543464, CpG_4543682, and CpG_4546888) to be significantly associated with three cis-mQTL SNPs (i.e., rs3758987, rs4938056, and rs1176744) located in our detected haplotype within HTR3B. In sum, we showed SNP rs1176744 (Tyr129Ser) to be associated with ND. Together with the SNPs rs3758987 and rs4938056 in HTR3B, they formed a major haplotype, which had significant association with ND. We further showed these SNPs contribute to ND through four methylated sites in HTR3B. 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. Nature Publishing Group UK 2018-11-07 /pmc/articles/PMC6221882/ /pubmed/30405098 http://dx.doi.org/10.1038/s41398-018-0290-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Han, Haijun Liu, Qiang Yang, Zhongli Wang, Mu Ma, Yunlong Cao, Liyu Cui, Wenyan Yuan, Wenji Payne, Thomas J. Li, Lanjuan Li, Ming D. Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers |
title | Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers |
title_full | Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers |
title_fullStr | Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers |
title_full_unstemmed | Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers |
title_short | Association and cis-mQTL analysis of variants in serotonergic genes associated with nicotine dependence in Chinese Han smokers |
title_sort | association and cis-mqtl analysis of variants in serotonergic genes associated with nicotine dependence in chinese han smokers |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221882/ https://www.ncbi.nlm.nih.gov/pubmed/30405098 http://dx.doi.org/10.1038/s41398-018-0290-8 |
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