The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies.
The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies.
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DOI：
10.1002/ajmg.b.30657
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发表时间：
2008-07-05
影响因子：
2.8
通讯作者：
Madan, Anup
中科院分区：
文献类型：
--
作者：
Philibert, Robert A.;Sandhu, Harinder;Hollenbeck, Nancy;Gunter, Tracy;Adams, William;Madan, Anup
5 -羟色胺转运蛋白（5HTTor SLC6A4） mRNA转录受遗传和表观遗传机制的调控。不幸的是，尽管经过严格的审查，这些调节机制的确切身份和贡献，以及它们与行为疾病的关系仍然未知。这种知识的缺乏是至关重要的，因为SLC6A4功能的改变被认为是各种中枢神经系统疾病的核心。为了解决这一缺陷，我们使用来自参加最新一波爱荷华收养研究的受试者的192个淋巴母细胞系的生物材料，量化了5HTTLPR基因型、SLC6A4 mRNA产生和CpG甲基化。然后，我们分析了有关临床特征的结果数据。我们证实了先前的研究结果，即短(s) 5HTTLPR等位基因与较低的mRNA转录量相关，但“长G”等位基因对mRNA转录没有显著影响。我们还发现，与男性相比，女性CpG甲基化更高（P< 0.0008）， mRNA产生更低（P< 0.0001）。终生有酒精依赖史的受试者SLC6A4 mRNA水平较高。总体甲基化增加与重度抑郁症的终生病史有关联的趋势。最后，我们证实了我们之前的发现，即5HTT mRNA表达的确切水平取决于它是如何测量的。我们认为遗传变异和表观遗传修饰都参与了SLC6A4功能的调控，并提示对控制基因活性的分子机制以及这些机制与行为疾病的关系进行更深入的研究。
Serotonin Transporter (5HTTor SLC6A4) mRNA transcription is regulated by both genetic and epigenetic mechanisms. Unfortunately, despite intense scrutiny, the exact identity and contribution of each of these regulatory mechanisms, and their relationship to behavioral illness remain unknown. This lack of knowledge is critical because alterations in SLC6A4 function are posited to be central to a wide variety of CNS disorders. In order to address this shortcoming, we quantified 5HTTLPR genotype, SLC6A4 mRNA production and CpG methylation using biomaterial from 192 lymphoblast cell lines derived from subjects who participated in the latest wave of the Iowa Adoption Studies. We then analyzed the resulting data with respect to clinical characteristics. We confirmed prior findings that the short (s) 5HTTLPR allele is associated with lower amounts of mRNA transcription, but there was no significant effect of the “Long G” allele on mRNA transcription. We also found that CpG methylation was higher (P< 0.0008) and mRNA production (P< 0.0001) was lower in females as compared to males. Those subjects with a lifetime history of Alcohol Dependence had higher levels of SLC6A4 mRNA. There was a trend for an association of increased overall methylation with lifetime history of major depression. Finally, we confirm our prior findings that the exact levels of 5HTT mRNA expression are dependent on how it is measured. We conclude that both genetic variation and epigenetic modifications contribute to the regulation of SLC6A4 function and that more in-depth studies of the molecular mechanisms controlling gene activity and the relationship of these mechanisms to behavioral illness are indicated.
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DOI：
10.1002/ajmg.b.30132
发表时间：
2005-02-05
影响因子：
2.8
作者：
Feinn, R;Nellissery, M;Kranzler, HR
通讯作者：
Kranzler, HR
DOI：
10.1080/10401230600948399
发表时间：
2006-10-01
期刊：
Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists
影响因子：
--
作者：
Philibert, Robert
通讯作者：
Philibert, Robert
影响因子：
9.8
作者：
Hu, XZ;Lipsky, RH;Goldman, D
通讯作者：
Goldman, D
影响因子：
--
作者：
Kendler, KS;Kuhn, JW;Riley, B
通讯作者：
Riley, B
影响因子：
56.9
作者：
Caspi, A;Sugden, K;Poulton, R
通讯作者：
Poulton, R