Department of Pharmacodynamics, Semmelweis University, 1089, Budapest, Hungary.
Proc Natl Acad Sci U S A. 2014 Apr 22;111(16):E1666-73. doi: 10.1073/pnas.1403649111. Epub 2014 Mar 24.
Galanin is a stress-inducible neuropeptide and cotransmitter in serotonin and norepinephrine neurons with a possible role in stress-related disorders. Here we report that variants in genes for galanin (GAL) and its receptors (GALR1, GALR2, GALR3), despite their disparate genomic loci, conferred increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events in a European white population cohort totaling 2,361 from Manchester, United Kingdom and Budapest, Hungary. Bayesian multivariate analysis revealed a greater relevance of galanin system genes in highly stressed subjects compared with subjects with moderate or low life stress. Using the same method, the effect of the galanin system genes was stronger than the effect of the well-studied 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Conventional multivariate analysis using general linear models demonstrated that interaction of galanin system genes with life stressors explained more variance (1.7%, P = 0.005) than the life stress-only model. This effect replicated in independent analysis of the Manchester and Budapest subpopulations, and in males and females. The results suggest that the galanin pathway plays an important role in the pathogenesis of depression in humans by increasing the vulnerability to early and recent psychosocial stress. Correcting abnormal galanin function in depression could prove to be a novel target for drug development. The findings further emphasize the importance of modeling environmental interaction in finding new genes for depression.
甘丙肽是一种应激诱导的神经肽和 5-羟色胺（5-HT）及去甲肾上腺素（NE）神经元的共递质，在应激相关障碍中可能发挥作用。在这里，我们报告了甘丙肽（GAL）及其受体（GALR1、GALR2、GALR3）基因的变异尽管位于不同的基因组位置，但在经历童年逆境或近期生活负性事件的欧洲白人群体队列中（英国曼彻斯特 2361 人，匈牙利布达佩斯 1000 人），与抑郁和焦虑风险增加相关。贝叶斯多变量分析显示，与生活应激程度中等到低度的受试者相比，甘丙肽系统基因在高应激受试者中具有更大的相关性。使用相同的方法，甘丙肽系统基因的作用强于已充分研究的 5-羟色胺转运体基因（SLC6A4）中的 5-HTTLPR 多态性。使用一般线性模型的常规多变量分析表明，甘丙肽系统基因与生活应激因素的相互作用比仅考虑生活应激的模型解释了更多的变异（1.7%，P = 0.005）。这一效应在曼彻斯特和布达佩斯亚群的独立分析以及男性和女性中得到了复制。这些结果表明，甘丙肽通路通过增加对早期和近期心理社会应激的易感性，在人类抑郁症的发病机制中发挥重要作用。纠正抑郁症中异常的甘丙肽功能可能被证明是开发新药物的一个新靶点。这些发现进一步强调了在寻找新的抑郁症基因时，对环境相互作用进行建模的重要性。
