Association of Polyaminergic Loci With Anxiety, Mood Disorders, and Attempted Suicide
Association of Polyaminergic Loci With Anxiety, Mood Disorders, and Attempted Suicide
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DOI：
10.1371/journal.pone.0015146
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发表时间：
2010-11-30
期刊：
影响因子：
3.7
通讯作者：
Turecki, Gustavo
中科院分区：
文献类型：
--
作者：
Fiori, Laura M.;Wanner, Brigitte;Turecki, Gustavo
背景资料：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多胺代谢相关基因表达的改变。研究已经确定了亚精胺/精胺N1-乙酰转移酶（SAT 1）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重要作用。方法学/主要发现：我们对63个多态性进行了基因分型，分布在4个多胺能基因中（SAT 1，精胺合酶（SMS），精胺氧化酶（SMOX），和鸟氨酸氨基转移酶样-1（OATL 1）），在1255法裔加拿大人谁已经纵向跟踪了22年。我们评估了成年早期与焦虑、情绪障碍和自杀未遂的单变量关联。我们还调查了基因-环境相互作用在儿童期虐待方面的参与，并评估了内化和外化症状作为介导这些相互作用的内表型。总体而言，每个基因与至少一个主要结果相关：焦虑（SAT 1，SMS），情绪障碍（SAT 1，SMOX）和自杀企图（SAT 1，OATL 1）。几个SAT 1多态性显示疾病特异性风险等位基因，该基因的多态性参与了与SMS的基因-基因相互作用，从而导致焦虑症的风险，以及儿童期身体虐待和情绪障碍之间的基因-环境相互作用。外化行为在OATL 1和自杀未遂之间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适当的内表型来解释与情绪或焦虑障碍的关联。最后，儿童期的性虐待没有表现出中介影响我们的任何outcome.Conclusions/Significance：这些结果表明，多胺能基因的遗传变异与精神疾病，其中每一个涉及一组单独的和不同的风险等位基因。由于这些多态性与基因表达相关，这些发现可能提供了解释在精神疾病中观察到的多胺代谢改变的机制。
Background: 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.