Battelle Center for Mathematical Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
J Child Psychol Psychiatry. 2013 Oct;54(10):1109-19. doi: 10.1111/jcpp.12119. Epub 2013 Aug 2.
Numerous studies have examined gene × environment interactions (G × E) in cognitive and behavioral domains. However, these studies have been limited in that they have not been able to directly assess differential patterns of gene expression in the human brain. Here, we assessed G × E interactions using two publically available datasets to assess if DNA variation is associated with post-mortem brain gene expression changes based on smoking behavior, a biobehavioral construct that is part of a complex system of genetic and environmental influences.
We conducted an expression quantitative trait locus (eQTL) study on two independent human brain gene expression datasets assessing G × E for selected psychiatric genes and smoking status. We employed linear regression to model the significance of the Gene × Smoking interaction term, followed by meta-analysis across datasets.
Overall, we observed that the effect of DNA variation on gene expression is moderated by smoking status. Expression of 16 genes was significantly associated with single nucleotide polymorphisms that demonstrated G × E effects. The strongest finding (p = 1.9 × 10⁻¹¹) was neurexin 3-alpha (NRXN3), a synaptic cell-cell adhesion molecule involved in maintenance of neural connections (such as the maintenance of smoking behavior). Other significant G × E associations include four glutamate genes.
This is one of the first studies to demonstrate G × E effects within the human brain. In particular, this study implicated NRXN3 in the maintenance of smoking. The effect of smoking on NRXN3 expression and downstream behavior is different based upon SNP genotype, indicating that DNA profiles based on SNPs could be useful in understanding the effects of smoking behaviors. These results suggest that better measurement of psychiatric conditions, and the environment in post-mortem brain studies may yield an important avenue for understanding the biological mechanisms of G × E interactions in psychiatry.
许多研究都考察了认知和行为领域的基因与环境相互作用（G×E）。然而，这些研究受到限制，因为它们无法直接评估人类大脑中基因表达的差异模式。在这里，我们使用两个公开的数据集来评估 G×E 相互作用，以评估 DNA 变异是否与吸烟行为相关，因为吸烟是遗传和环境影响的复杂系统的一部分，是一种生物行为结构。
我们对两个独立的人类大脑基因表达数据集进行了表达数量性状基因座（eQTL）研究，评估了选定的精神基因和吸烟状况的 G×E。我们采用线性回归来构建基因与吸烟相互作用项的显著性模型，然后对数据集进行元分析。
总体而言，我们观察到 DNA 变异对基因表达的影响受到吸烟状况的调节。有 16 个基因的表达与表现出 G×E 效应的单核苷酸多态性显著相关。最强的发现（p=1.9×10⁻¹¹）是神经素 3-α（NRXN3），这是一种突触细胞-细胞粘附分子，参与维持神经连接（如吸烟行为的维持）。其他重要的 G×E 关联包括四个谷氨酸基因。
这是第一个在人类大脑中证明 G×E 效应的研究之一。特别是，本研究表明 NRXN3 在吸烟的维持中起作用。吸烟对 NRXN3 表达和下游行为的影响因 SNP 基因型而异，这表明基于 SNP 的 DNA 谱可能有助于理解吸烟行为的影响。这些结果表明，在死后大脑研究中更好地测量精神状况和环境可能为理解精神病学中 G×E 相互作用的生物学机制提供一个重要途径。
