Leveraging brain cortex-derived molecular data to elucidate epigenetic and transcriptomic drivers of neurological function and disease
Leveraging brain cortex-derived molecular data to elucidate epigenetic and transcriptomic drivers of neurological function and disease
复制标题
利用大脑皮层衍生的分子数据来阐明神经功能和疾病的表观遗传和转录组驱动因素
DOI：
10.1101/429134
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Hatcher C
中科院分区：
文献类型：
--
作者：
Hatcher C
利用多个大规模分子数据集的综合方法可以帮助开发对全基因组关联研究（GWAS）结果的机制见解。我们已经进行了广泛的分析，以揭示转录和表观遗传机制，可能发挥作用的神经学性状variation.This是通过应用贝叶斯多性状共定位系统的基因组，以确定遗传变异，负责影响神经学性状以及中间分子表型。为了实现这一点，我们利用了来自前额叶皮层组织的高维数量性状基因座数据，（关于基因表达，DNA甲基化和组蛋白乙酰化）和GWAS发现的5个神经学特征（神经质，精神分裂症，教育程度，阿尔茨海默病（Alzheimer's disease）有证据表明，118个协会的共定位表明，相同的潜在遗传变异影响了当地的基因表达，以及神经学特征变异。其中，73个关联提供了遗传变异也影响近端DNA甲基化和/或组蛋白乙酰化的证据。这些发现支持了先前的证据，即表观遗传机制可能会介导遗传变异对性状的影响，如KLC 1和精神分裂症。我们还发现了新的神经系统疾病易感性基因位点，包括主要在脑组织中表达的基因如MDGA 1、KIRGA 3和SLC 12 A5。DNA甲基化与基因表达之间的负相关性超过了偶然性，支持了先前的研究结果，即DNA甲基化是一种转录抑制因子。我们的研究应该证明是有价值的，有助于未来的研究优先考虑候选基因和表观遗传机制，以进行深入的功能随访分析。
Integrative approaches which harness multiple large-scale molecular datasets can help develop mechanistic insight into findings from genome-wide association studies (GWAS). We have performed extensive analyses to uncover transcriptional and epigenetic mechanisms which may play a role in neurological trait variation.This was undertaken by applying a Bayesian multiple-trait colocalization systematically across the genome to identify genetic variants which are responsible for influencing neurological traits as well as intermediate molecular phenotypes. To achieve this, we leveraged high dimensional quantitative trait loci data derived from prefrontal cortex tissue (concerning gene expression, DNA methylation and histone acetylation) and GWAS findings for 5 neurological traits (Neuroticism, Schizophrenia, Educational Attainment, Insomnia and Alzheimer’s disease).There was evidence of colocalization for 118 associations suggesting that the same underlying genetic variant influenced both local gene expression as well as neurological trait variation. Of these, 73 associations provided evidence that the genetic variant also influenced proximal DNA methylation and/or histone acetylation. These findings support previous evidence at loci where epigenetic mechanisms may putatively mediate effects of genetic variants on traits, such asKLC1and schizophrenia. We also uncovered evidence implicating novel loci in neurological disease susceptibility, including genes expressed predominantly in brain tissue such asMDGA1, KIRREL3andSLC12A5.An inverse relationship between DNA methylation and gene expression was observed more than can be accounted for by chance, supporting previous findings implicating DNA methylation as a transcriptional repressor. Our study should prove valuable in helping future studies prioritise candidate genes and epigenetic mechanisms for in-depth functional follow-up analyses.
登录
查看更多内容
影响因子：
4.4
作者：
Sparding T;Pålsson E;Joas E;Hansen S;Landén M
通讯作者：
Landén M
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
通过表观基因组操作揭示启动子 DNA 甲基化的全基因组抑制能力
DOI：
--
发表时间：
2018
期刊：
bioRxiv
影响因子：
--
作者：
Keegan D. Korthauer;R. Irizarry
通讯作者：
R. Irizarry
影响因子：
9.8
作者：
Hannon E;Weedon M;Bray N;O'Donovan M;Mill J
通讯作者：
Mill J
影响因子：
4.4
作者：
Yu, Chang-En;Seltman, Howard;Schellenberg, Gerard D.
通讯作者：
Schellenberg, Gerard D.