Backgorund

Increasing experimental data confirm the crucial role of the endocannabinoid (eCB) system in the regulation of stress response and emotional processes. Despite of the fact, that genetically determined vulnerability for stress is a widely accepted concept in the pathomechanism of affective disorders, replicable human genetic results with interaction analyses of early life trauma and eCB genes are rare. The aim of this study is to test the associations between genetic variants of the eCB pathway, childhood trauma and affective phenotypes.

Methods

We selected 18897 SNPs in the eCB pathway of a GWAS dataset in two general population cohorts (BP sample N = 837; MN sample N = 988). Association analyses were performed on the anxious and depressive subscales of the Brief Symptom Inventory (BSI-ANX and BSI-DEP, respectively). Childhood trauma was assessed by the Childhood Adversity Questionnaire (CAQ). Association analyses were performed in the R 2.0. statistical program using the SNPassoc package.

Reults

Genetic effect was more robust in the BP sample than in the MN sample. The most comprehensive results showed that SNPs in the CACNA1C gene associated with depressive phenotype in interaction with CAQ in both BP (p = 1.2x10-⁴) and MN samples (p = 1.6x10^-4). Direct association analyses (without interaction) provided significant associations between SNPs in different genesets of the two study populations. SNPs in KCNJ3 and GNB5 genes on the BSI-DEP (p = 6.1 × 10^-5; p = 7.1 × 10^-4) and GNG12 gene on the BSI-ANX (p = 7.4 × 10^-6) in the BP sample, while GABAergic, ADCY1 and HTR2A gene variants can be outlined from results of MN sample with less strong p-values.

Conclusion

Our results confirmed the prominent role of CACNA1C gene in the pathogenic effect of early life stress in the development of affective vulnerability in two different study populations using GxE interaction analysis. CACNA1C gene, as it encodes for L-type voltage-gated calcium channel, contributes to neuronal excitability, plasticity and neurogenesis being a crucial effector of both eCB signaling and the BDNF-CREB pathway as well. Our findings suggest that childhood trauma related depression may have more robust genetically determined basis than without early life stress.

中文翻译：

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内源性大麻素途径与情感表型变异的遗传分析

Backgorund

越来越多的实验数据证实了内源性大麻素（eCB）系统在调节压力反应和情绪过程中的关键作用。尽管存在这样的事实，即遗传确定的应激易感性在情感障碍的发病机理中是一个广为接受的概念，但具有早期生命创伤和eCB基因相互作用分析的可复制的人类遗传结果却很少。这项研究的目的是测试eCB途径的遗传变异，儿童期创伤和情感表型之间的关联。

方法

我们在两个普通人群的GWAS数据集的eCB途径中选择了18897个SNP（BP样本N = 837； MN样本N = 988）。对简短症状量表的焦虑和抑郁量表（分别为BSI-ANX和BSI-DEP）进行了关联分析。儿童创伤由《儿童逆境问卷》（CAQ）评估。关联分析是在R 2.0中进行的。使用SNPassoc软件包的统计程序。

结果

BP样品中的遗传效应比MN样品中的遗传效应更强。最全面的结果表明，单核苷酸多态性在CACNA1C与相互作用在两个BP抑郁表型与CAQ（相关基因p  = 1.2x10- ⁴）和MN样品（p  = 1.6×10 ^-4）。直接关联分析（无相互作用）在两个研究人群的不同基因组中提供了SNP之间的显着关联。BSI-DEP上的KCNJ3和GNB5基因中的SNP （p = 6.1×10 ^-5 ; p = 7.1×10 ^-4）和BSI-ANX上的GNG12基因（p = 7.4×10 ^-6），而BP样本中的GABAergic，ADCY1和HTR2A基因变体则可以从MN样本的结果中以较低的p值概括出来。

结论

我们的结果证实了CACNA1C基因在早期生活压力的致病作用中在两个不同研究人群的情感脆弱性发展中的显著作用，采用GxE相互作用分析。CACNA1C基因编码L型电压门控钙通道，有助于神经元兴奋性，可塑性和神经发生，是eCB信号传导和BDNF-CREB途径的关键效应器。我们的发现表明，与没有早期生活压力的情况相比，与儿童创伤相关的抑郁症可能具有更强大的遗传基础。