Davidson S, Shanley L, Cowie P, Lear M, McGuffin P, Quinn J P, Barrett P, MacKenzie A
School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
Social, Genetic and Developmental Psychiatry Centre (MRC), Institute of Psychiatry, Psychology and Neuroscience, Denmark Hill, London, UK.
Pharmacogenomics J. 2016 Aug;16(4):366-74. doi: 10.1038/tpj.2015.62. Epub 2015 Oct 6.
The Bicaudal C Homolog 1 (BICC1) gene, which encodes an RNA binding protein, has been identified by genome wide association studies (GWAS) as a candidate gene associated with major depressive disorder (MDD). We explored the hypothesis that MDD associated single-nucleotide polymorphisms (SNPs) affected the ability of cis-regulatory elements within intron 3 of the BICC1 gene to modulate the activity of the BICC1 promoter region. We initially established that the BICC1 promoter drove BICC1 mRNA expression in amygdala, hippocampus and hypothalamus. Intriguingly, we provide evidence that MDD associated polymorphisms alter the ability of the BICC1 promoter to respond to PKA signalling within amygdala neurones. Considering the known role of amygdala PKA pathways in fear learning and mood these observations suggest a possible mechanism through which allelic changes in the regulation of the BICC1 gene in amygdala neurones may contribute to mood disorders. Our findings also suggest a novel direction for the identification of novel drug targets and the design of future personalised therapeutics.The Pharmacogenomics Journal advance online publication, 6 October 2015; doi:10.1038/tpj.2015.62.
双尾C同源物1（BICC1）基因编码一种RNA结合蛋白，通过全基因组关联研究（GWAS）已将其鉴定为与重度抑郁症（MDD）相关的候选基因。我们探讨了以下假说：与MDD相关的单核苷酸多态性（SNP）影响BICC1基因第3内含子内顺式调控元件调节BICC1启动子区域活性的能力。我们最初证实BICC1启动子在杏仁核、海马体和下丘脑驱动BICC1 mRNA表达。有趣的是，我们提供的证据表明，与MDD相关的多态性改变了BICC1启动子对杏仁核神经元内PKA信号作出反应的能力。鉴于杏仁核PKA通路在恐惧学习和情绪方面的已知作用，这些观察结果提示了一种可能的机制，通过该机制，杏仁核神经元中BICC1基因调控的等位基因变化可能导致情绪障碍。我们的研究结果还为鉴定新型药物靶点和设计未来的个性化治疗方法指明了一个新方向。《药物基因组学杂志》在线优先发表，2015年10月6日；doi:10.1038/tpj.2015.62
