...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Pharmacogenomics >Epigenomic mapping and effect sizes of noncoding variants associated with psychotropic drug response
【24h】

Epigenomic mapping and effect sizes of noncoding variants associated with psychotropic drug response

机译：精神药物反应相关的非编码变体的表观基因组定位和效应大小

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Aim: To provide insight into potential regulatory mechanisms of gene expression underlying addiction, analgesia, psychotropic drug response and adverse drug events, genome-wide association studies searching for variants associated with these phenotypes has been undertaken with limited success. We undertook analysis of these results with the aim of applying epigenetic knowledge to aid variant discovery and interpretation. Methods: We applied conditional imputation to results from 26 genome-wide association studies andthree candidate gene-association studies. The analysis workflow included data from chromatin conformation capture, chromatin state annotation, DNase I hypersensitivity, hypomethylation, anatomical localization and biochronicity. We also made use of chromatin state data from the epigenome roadmap, transcription factor-binding data, spatial maps from published Hi-C datasets and guilt by association' methods. Results: We identified 31 pharmacoepigenomic SNPs from a total of 2024 variants in linkage disequilibrium with lead SNPs, of which only 6% were coding variants. Interrogation of chromatin state using our workflow and the epigenome roadmap showed agreement on 34 of 35 tissue assignments to regulatory elements including enhancers and promoters. Loop boundary domains were inferred by association with CTCF (CCCTC-binding factor) and cohesin, suggesting proximity to topologically associating domain boundaries and enhancer clusters. Spatial interactions between enhancer-promoter pairs detected both known and previously unknown mechanisms. Addiction and analgesia SNPs were common in relevant populations and exhibited large effect sizes, whereas a SNP located in the promoter of the SLC1A2 gene exhibited a moderate effect size for lithium response in bipolar disorder in patients of European ancestry. SNPs associated with drug-induced organ injury were rare but exhibited the largest effect sizes, consistent with the published literature. Conclusion: This work demonstrates that an in silico bioinformatics-based approach using integrative analysis of a diversity of molecular and morphological data types can discover pharmacoepigenomic variants that are suitable candidates for further validation in cell lines, animal models and human clinical trials.
机译：目的：为了深入了解成瘾，镇痛，精神药物反应和药物不良反应的潜在基因表达调控机制，进行了与这些表型相关的变异的全基因组关联研究，取得了有限的成功。我们对这些结果进行了分析，目的是应用表观遗传学知识来帮助变体发现和解释。方法：我们对26个全基因组关联研究和3个候选基因关联研究的结果应用了条件推算。分析工作流程包括来自染色质构象捕获，染色质状态注释，DNase I过敏，甲基化不足，解剖学定位和生物时空性的数据。我们还利用了表观基因组路线图上的染色质状态数据，转录因子结合数据，已发布的Hi-C数据集上的空间图以及通过关联方法产生的内感。结果：我们从总共2024个与前导SNP连锁不平衡的变体中鉴定出31种药效基因组SNP，其中只有6％是编码变体。使用我们的工作流程和表观基因组路线图对染色质状态的询问表明，在35个组织中有34个分配给调控元件（包括增强子和启动子）方面达成了一致。环边界域是通过与CTCF（CCCTC结合因子）和粘着蛋白的结合来推断的，表明与拓扑关联的域边界和增强子簇的接近性。增强子-启动子对之间的空间相互作用检测到已知和以前未知的机制。成瘾和镇痛SNPs在相关人群中很常见，并且显示出较大的效应大小，而位于SLC1A2基因启动子上的SNP在欧洲血统的双相情感障碍患者中显示出适度的锂反应效应大小。与药物诱导的器官损伤相关的SNP很少见，但表现出最大的效应值，与已发表的文献一致。结论：这项工作表明，采用基于计算机生物信息学的方法对多种分子和形态学数据类型进行综合分析，可以发现药物表观基因组变异体，这些变异体适合在细胞系，动物模型和人类临床试验中进一步验证。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号