McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
PLoS One. 2010 Nov 30;5(11):e15146. doi: 10.1371/journal.pone.0015146.
The polyamine system has been implicated in a number of psychiatric conditions, which display both alterations in polyamine levels and altered expression of genes related to polyamine metabolism. Studies have identified associations between genetic variants in spermidine/spermine N1-acetyltransferase (SAT1) and both anxiety and suicide, and several polymorphisms appear to play important roles in determining gene expression.
METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 63 polymorphisms, spread across four polyaminergic genes (SAT1, spermine synthase (SMS), spermine oxidase (SMOX), and ornithine aminotransferase like-1 (OATL1)), in 1255 French-Canadian individuals who have been followed longitudinally for 22 years. We assessed univariate associations with anxiety, mood disorders, and attempted suicide, as assessed during early adulthood. We also investigated the involvement of gene-environment interactions in terms of childhood abuse, and assessed internalizing and externalizing symptoms as endophenotypes mediating these interactions. Overall, each gene was associated with at least one main outcome: anxiety (SAT1, SMS), mood disorders (SAT1, SMOX), and suicide attempts (SAT1, OATL1). Several SAT1 polymorphisms displayed disease-specific risk alleles, and polymorphisms in this gene were involved in gene-gene interactions with SMS to confer risk for anxiety disorders, as well as gene-environment interactions between childhood physical abuse and mood disorders. Externalizing behaviors demonstrated significant mediation with regards to the association between OATL1 and attempted suicide, however there was no evidence that externalizing or internalizing behaviors were appropriate endophenotypes to explain the associations with mood or anxiety disorders. Finally, childhood sexual abuse did not demonstrate mediating influences on any of our outcomes.
CONCLUSIONS/SIGNIFICANCE: These results demonstrate that genetic variants in polyaminergic genes are associated with psychiatric conditions, each of which involves a set of separate and distinct risk alleles. As several of these polymorphisms are associated with gene expression, these findings may provide mechanisms to explain the alterations in polyamine metabolism which have been observed in psychiatric disorders.
多胺系统与许多精神疾病有关，这些疾病表现为多胺水平的改变和与多胺代谢相关的基因表达改变。研究已经确定了精脒/精脒 N1-乙酰基转移酶（SAT1）基因中的遗传变异与焦虑和自杀之间的关联，并且几种多态性似乎在决定基因表达方面发挥着重要作用。
方法/主要发现：我们对横跨四个多胺能基因（SAT1、精脒合酶（SMS）、精脒氧化酶（SMOX）和鸟氨酸氨基转移酶样-1（OATL1））的 63 个多态性进行了基因分型，这些多态性分布在 1255 名法裔加拿大个体中，这些个体已经被纵向跟踪了 22 年。我们评估了与焦虑、心境障碍和年轻时尝试自杀的单变量关联。我们还研究了童年期虐待的基因-环境相互作用的参与情况，并评估了作为这些相互作用中介的内化和外化症状的内表型。总体而言，每个基因都与至少一个主要结局相关：焦虑（SAT1、SMS）、心境障碍（SAT1、SMOX）和自杀未遂（SAT1、OATL1）。SAT1 的几个多态性显示出疾病特异性风险等位基因，并且该基因中的多态性与 SMS 发生基因-基因相互作用，从而增加了焦虑障碍的风险，以及童年期身体虐待与心境障碍之间的基因-环境相互作用。外化行为在 OATL1 与自杀未遂的关联中表现出显著的中介作用，但是没有证据表明外化或内化行为是解释与心境或焦虑障碍相关的适当内表型。最后，童年期性虐待并没有对我们的任何结果表现出中介作用。
结论/意义：这些结果表明，多胺能基因中的遗传变异与精神疾病有关，每种疾病都涉及一组单独和不同的风险等位基因。由于这些多态性中的一些与基因表达有关，这些发现可能为解释在精神疾病中观察到的多胺代谢改变提供机制。
