Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland.
Am J Med Genet B Neuropsychiatr Genet. 2010 Jun 5;153B(4):909-18. doi: 10.1002/ajmg.b.31059.
Serotonergic signaling abnormalities have been implicated in suicide. Tryptophan hydroxylase (TPH), the rate limiting enzyme of serotonin biosynthesis and the serotonin transporter (SLC6A4), involved in the reuptake of serotonin from the synaptic gap, play major role in serotonergic signaling. In this study, we aimed to compare the levels of expression of these serotonin-related genes between suicide completers and controls and to identify genetic loci involved in their regulation. SLC6A4, TPH1, and TPH2 mRNA levels were measured in the ventral prefrontal cortex (VPFC) of 39 suicide completers and 40 matched controls. To identify the molecular basis of gene expression variation, we performed association studies between cis-acting polymorphisms and SLC6A4, TPH1, and TPH2 transcript levels. Finally, association analyses were carried out between suicide and TPH2 cis-single nucleotide polymorphisms (SNPs) in cohorts of 154 suicide completers and 289 control subjects. Whereas SLC6A4 and TPH1 mRNA expression levels did not differ between suicides and controls, TPH2 levels were found significantly increased (P = 0.003) in suicide completers. We observed that SNP rs10748185 located in the promoter region of TPH2 significantly affect levels of TPH2 mRNA expression. However, we did not find positive association between this eQTL (rs10748185) and suicide. Here, we report the simultaneous analysis of the expression of three serotonin-related genes in the VPFC of suicide victims and controls. This study showed that TPH2 expression levels were increased in the VPFC of suicide victims. Although, we identified a genetic variant that explains variance in TPH2 expression, we did not find evidence associating this cis-regulatory SNP with suicidal behavior.
血清素能信号异常与自杀有关。色氨酸羟化酶（TPH）是 5-羟色胺生物合成的限速酶，5-羟色胺转运体（SLC6A4）参与 5-羟色胺从突触间隙的再摄取，它们在血清素能信号中发挥主要作用。在这项研究中，我们旨在比较自杀者和对照组之间这些与 5-羟色胺相关基因的表达水平，并确定参与其调控的遗传位点。在 39 名自杀者和 40 名匹配的对照者的腹侧前额叶皮质（VPFC）中测量了 SLC6A4、TPH1 和 TPH2 的 mRNA 水平。为了确定基因表达变异的分子基础，我们在 SLC6A4、TPH1 和 TPH2 转录物水平与顺式作用多态性之间进行了关联研究。最后，在 154 名自杀者和 289 名对照者的队列中进行了 TPH2 顺式单核苷酸多态性（SNP）与自杀的关联分析。尽管 SLC6A4 和 TPH1 的 mRNA 表达水平在自杀者和对照组之间没有差异，但 TPH2 的水平在自杀者中发现明显升高（P=0.003）。我们观察到位于 TPH2 启动子区域的 SNP rs10748185 显著影响 TPH2 mRNA 表达水平。然而，我们没有发现这个 eQTL（rs10748185）与自杀之间存在正相关。在这里，我们报告了在自杀受害者和对照组的 VPFC 中同时分析三个与 5-羟色胺相关的基因的表达。这项研究表明，TPH2 的表达水平在自杀者的 VPFC 中增加。尽管我们确定了一个解释 TPH2 表达变异性的遗传变异，但我们没有发现与自杀行为相关的顺式调节 SNP 的证据。
