NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Simula Research Laboratory and Center for Cardiological Innovation, Oslo, Norway.
Transl Psychiatry. 2017 Nov 17;7(11):5. doi: 10.1038/s41398-017-0007-4.
Schizophrenia patients have an increased risk of cardiac dysfunction. A possible factor underlying this comorbidity are the common variants in the large set of genes that have recently been discovered in genome-wide association studies (GWASs) as risk genes of schizophrenia. Many of these genes control the cell electrogenesis and calcium homeostasis. We applied biophysically detailed models of layer V pyramidal cells and sinoatrial node cells to study the contribution of schizophrenia-associated genes on cellular excitability. By including data from functional genomics literature to simulate the effects of common variants of these genes, we showed that variants of voltage-gated Na channel or hyperpolarization-activated cation channel-encoding genes cause qualitatively similar effects on layer V pyramidal cell and sinoatrial node cell excitability. By contrast, variants of Ca channel or transporter-encoding genes mostly have opposite effects on cellular excitability in the two cell types. We also show that the variants may crucially affect the propagation of the cardiac action potential in the sinus node. These results may help explain some of the cardiac comorbidity in schizophrenia, and may facilitate generation of effective antipsychotic medications without cardiac side-effects such as arrhythmia.
精神分裂症患者患心脏功能障碍的风险增加。这种合并症的一个可能因素是，在全基因组关联研究 (GWAS) 中发现的与精神分裂症风险基因相关的大型基因集中的常见变异。这些基因中的许多基因控制着细胞的电发生和钙稳态。我们应用了具有生物物理细节的 V 层锥体神经元和窦房结细胞模型，研究了与精神分裂症相关的基因对细胞兴奋性的贡献。通过纳入功能基因组学文献中的数据来模拟这些基因常见变异的影响，我们表明，电压门控钠通道或超极化激活阳离子通道编码基因的变异对 V 层锥体神经元和窦房结细胞兴奋性产生定性相似的影响。相比之下，钙通道或转运蛋白编码基因的变异在两种细胞类型中对细胞兴奋性的影响大多相反。我们还表明，这些变异可能会严重影响窦房结中心脏动作电位的传播。这些结果可能有助于解释精神分裂症中的一些心脏合并症，并可能有助于生成没有心律失常等心脏副作用的有效抗精神病药物。
