Alaerts Maaike, Ceulemans Shana, Forero Diego, Moens Lotte N, De Zutter Sonia, Heyrman Lien, Lenaerts An-Sofie, Norrback Karl-Fredrik, Goossens Dirk, De Rijk Peter, Nilsson Lars-Göran, Adolfsson Rolf, Del-Favero Jurgen
Applied Molecular Genomics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.
Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 5;150B(4):585-92. doi: 10.1002/ajmg.b.30853.
Through active reuptake of serotonin into presynaptic neurons, the serotonin transporter (5-HTT) plays an important role in regulating serotonin concentrations in the brain, and it is the site of binding for tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). Therefore it has been hypothesized that this transporter is involved in the etiology of bipolar (BP) disorder. Inconsistent association study results for the SLC6A4 gene encoding 5-HTT reported in literature emphasize the need for more systematic and detailed analyses of this candidate gene. We performed an extensive analysis of SLC6A4 on DNA of 254 BPI patients and 364 control individuals from a Northern Swedish isolated population. This analysis consisted of a HapMap LD-based association study including three widely investigated polymorphisms (5-HTTVNTR, 5-HTTLPR, and rs3813034), a copy-number variation (CNV) analysis and a mutation analysis of the complete coding sequence and the 3'-UTR of SLC6A4. No single marker showed statistically significant association with BPI, nor did any of the haplotypes. In the mutation analysis 13 novel variants were detected, including 2 amino acid substitutions M389V and I587L, but these are probably not implicated in risk for BP. No deletions or duplications were detected in the CNV analysis. We conclude that variation in the SLC6A4 gene or its regulatory regions does not contribute to the susceptibility for BP disorder in the Northern Swedish population.
通过将血清素主动重摄取到突触前神经元中，血清素转运体（5-HTT）在调节大脑中血清素浓度方面发挥着重要作用，并且它是三环类抗抑郁药和选择性血清素再摄取抑制剂（SSRI）的结合位点。因此，有人推测该转运体与双相情感障碍（BP）的病因有关。文献中报道的关于编码5-HTT的SLC6A4基因的关联研究结果不一致，这强调了对该候选基因进行更系统、详细分析的必要性。我们对来自瑞典北部隔离人群的254例双相情感障碍I型（BPI）患者和364名对照个体的DNA进行了SLC6A4的广泛分析。该分析包括一项基于HapMap连锁不平衡的关联研究，其中包括三个广泛研究的多态性（5-HTTVNTR、5-HTTLPR和rs3813034）、一项拷贝数变异（CNV）分析以及对SLC6A4完整编码序列和3'-UTR的突变分析。没有单个标记显示与BPI有统计学上的显著关联，单倍型也没有。在突变分析中检测到13个新变体，包括2个氨基酸替代M389V和I587L，但这些可能与BP风险无关。在CNV分析中未检测到缺失或重复。我们得出结论，SLC6A4基因或其调控区域的变异对瑞典北部人群中BP障碍的易感性没有影响。
