| 1 | Pharmacogenomics 2011 Feb 12: 171-84 |
|---|---|
| PMID | 21332311 |
| 标题 | Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker. |
| 抽象的 | Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressants for treating major depression. However, approximately 30% of patients do not respond sufficiently to first-line antidepressant drug treatment and require alternative therapeutics. Genome-wide studies searching for SSRI response DNA biomarkers or studies of candidate serotonin-related genes so far have given inconclusive or contradictory results. Here, we present an alternative transcriptome-based genome-wide approach for searching antidepressant drug-response biomarkers by using drug-effect phenotypes in human lymphoblastoid cell lines (LCLs). We screened 80 LCLs from healthy adult female individuals for growth inhibition by paroxetine. A total of 14 LCLs with reproducible high and low sensitivities to paroxetine (seven from each phenotypic group) were chosen for genome-wide expression profiling with commercial microarrays. 表现出较高的LCL与低帕罗西汀敏感性之间的最显着的全基因组转录组差异是CHL1的基础表达低6.3倍（P = 0.0000256），该基因是编码在正确的丘脑皮层回路中的神经元细胞粘附蛋白的基因，该基因编码为神经元细胞粘附蛋白，schizophrenia和自闭症。通过实时PCR（高帕罗西汀敏感性组中CHL1表达水平较低36倍）证实了微阵列的发现。与突触发生或精神疾病有关的其他基因，包括ARRB1，CCL5，DDX60，DDX60L，endod1，enpp2，FLT1，GABRA4，GAP43，MCTP2和SPRY2，在两个Paroxetine敏感性组之间也差异超过1.5倍，P值小于0.005，如实时PCR实验所证实。 全基因组全基因组的转录分析鉴定出CHL1和与突触发生和脑电路有关的其他基因作为推定的SSRI反应生物标志物。该方法可以用作寻找潜在抑郁症治疗生物标志物的初步工具。 |
| SCZ关键字 | schizophrenia |
| 2 | Front Behav Neurosci 2014 -1 8: 110 |
| PMID | 24765068 |
| 标题 | Medial prefrontal cortex: genes linked to bipolar disorder and schizophrenia have altered expression in the highly social maternal phenotype. |
| 抽象的 | 过渡到母亲是CNS changes that modify sociability and affective state. However, these changes also put females at risk for post-partum depression and psychosis, which impairs parenting abilities and adversely affects children. Thus, changes in expression and interactions in a core subset of genes may be critical for emergence of a healthy maternal phenotype, but inappropriate changes of the same genes could put women at risk for post-partum disorders. This study evaluated microarray gene expression changes in medial prefrontal cortex (mPFC), a region implicated in both maternal behavior and psychiatric disorders. Post-partum mice were compared to virgin controls housed with females and isolated for identical durations. Using the Modular Single-set Enrichment Test (MSET), we found that the genetic landscape of maternal mPFC bears statistical similarity to gene databases associated withschizophrenia(5 of 5 sets) and bipolar disorder (BPD, 3 of 3 sets). In contrast to previous studies of maternal lateral septum (LS) and medial preoptic area (MPOA), enrichment of autism and depression-linked genes was not significant (2 of 9 sets, 0 of 4 sets). Among genes linked to multiple disorders were fatty acid binding protein 7 (Fabp7), glutamate metabotropic receptor 3 (Grm3), platelet derived growth factor, beta polypeptide (Pdgfrb), and nuclear receptor subfamily 1, group D, member 1 (Nr1d1). RT-qPCR confirmed these gene changes as well as FMS-like tyrosine kinase 1 (FLT1) and proenkephalin (Penk). Systems-level methods revealed involvement of developmental gene networks in establishing the maternal phenotype and indirectly suggested a role for numerous microRNAs and transcription factors in mediating expression changes. Together, this study suggests that a subset of genes involved in shaping the healthy maternal brain may also be dysregulated in mental health disorders and put females at risk for post-partum psychosis with aspects ofschizophreniaand BPD. |
| SCZ关键字 | schizophrenia |
| 3 | Gene 2015 Nov 572: 175-83 |
| PMID | 26149656 |
| 标题 | Role of long purine stretches in controlling the expression of genes associated with neurological disorders. |
| 抽象的 | Purine repeat sequences present in the human genome are known to act as hotspots for mutations leading to chromosomal imbalances. It is established that large purine repeats (PRs) form stable DNA triplex structure which can inhibit gene expression. Friedreich's ataxia (FRDA), the autosomal neurodegenerative disorder is the only human disease known so far, where a large purine (GAA) repeat in the FXN gene is known to inhibit the expression of frataxin protein. We explored the hidden purine repeats (PRn with n ? 200) if any, in the human genome to find out how they are associated with neurological disorders. The results showed 28 PRs, which are mostly restricted to the intronic regions. Interestingly, the transcriptome expression analysis of PR-carrying genes (PR-genes) revealed that most of them are down-regulated in neurological disorders (autism, Alzheimer's disease,schizophrenia，与健康对照组相比，癫痫，智力低下，帕金森氏病，脑肿瘤）。可以用嘌呤重复的扩展来解释脑疾病中基因表达的改变，从而导致形成非常稳定的DNA-TRIPLEX和/或减轻修复酶和/或其他未知细胞因子。Interactome分析在信号通路中确定了四个PR生成，其失调与发病机理直接相关：Alzheimer病中的GRK5和KLK6；FGF14在颅突尼斯变性，智力低下和FLT1in neuroferritinopathy. By virtue of being mutational hotspots and their ability to form DNA-triplex, purine repeats in genome disturb the genome integrity and interfere with the transcriptional regulation. However, validation of the disease linkage of PR-genes can be validated using knock-out techniques. |
| SCZ关键字 | schizophrenia |