Mediators of methylomic profiles in 1500 schizophrenia cases and controls
1500 例精神分裂症病例和对照中甲基组谱的调节因子
基本信息
- 批准号:8623579
- 负责人:
- 金额:$ 7.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-01 至 2015-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAffectAffinityAge of OnsetAlgorithmsAntipsychotic AgentsApgar ScoreBioinformaticsBiologicalBiological MarkersBirthBirth RecordsBrainComplementComplexDNADNA MethylationDNA Sequence AnalysisDataData SetDiagnosisDiseaseDrug PrescriptionsEnsureEnvironmentEnvironmental ExposureFamilyFutureGene ExpressionGeneticGenetic PolymorphismGenomeGenotypeGoalsHumanHuman GenomeHypoxiaImmune responseIndividualInfectionKnowledgeLeadLifeLocationLongitudinal StudiesMediator of activation proteinMethylationNaturePathogenesisPathway AnalysisPatientsPharmaceutical PreparationsPharmacologic SubstancePhenotypePlayPredispositionProtein Binding DomainQuantitative Trait LociRegulationRegulatory ElementResearchRoleSamplingSampling StudiesSavingsSchizophreniaSignal TransductionSiteSocietiesTimeVariantbasebisulfitecase controlcohortdata integrationexomeexome sequencingfollow-upgene environment interactiongenetic variantgenome wide association studygenome-wideimprovedinsightmRNA Expressionmethylomeneuropsychiatrynext generation sequencingnoveloutcome forecastpublic health relevancepyrosequencingresponsesex
项目摘要
Schizophrenia (SZ) is an often-devastating neuropsychiatric illness. Genetic factors have been strongly
implicated. The genetic contribution to SZ is likely to be complex and to extend beyond sequence variation.
DNA methylation studies represent a promising complement to analyses of DNA sequence. As methylation is
related to gene expression, knowledge of methylation levels of, e.g., regulatory elements may contribute
functional information. Furthermore, as DNA methylation changes over time, methylation studies can provide
insight into phenomena such as age of onset and the episodic nature of SZ. In addition, the dynamic nature of
methylation and its response to environmental exposures suggests that methylation may explain gene-
environment interactions.
In a recent study, including 1,500 SZ case-control samples, all CpGs in the methylome was investigated
using the enrichment based MBD-seq approach. This approach employs a methyl-CpG binding domain protein
with high affinity for methylated CpGs in combination with next-generation sequencing to investigate the
methylation profile across all CpGs in the genome. The data was used to conduct a methylome-wide
association study (MWAS) covering ~27 million CpGs in the autosomal human reference genome. Analysis of
SZ case-control status resulted in significant CpGs of promising biological relevance such as hypoxia and
immune response. The results where successfully replicated in an independent study-sample using highly
quantitative bisulfite pyrosequencing.
The current proposal aims to conduct new analysis of the methylome data. Phenotype information about
birth complications (e.g., hypoxia and infection), and use of prescribed drugs, such as antipsychotics, as well
as genotype information from GWAS SNP genotyping, exome-sequencing and exome-chips are available from
the study sample, which will be used in the new analysis. The human genome consists of a large number of
CpGs that are created/destroyed by SNPs. Using the MBD-seq approach the methylation status for these
CpGs are already available. However, the analyses for these sites require a different approach than CpGs in
general. By integrating methylation and SNP information the methylation signal in these sites can be
investigated conditional on the sequence and the potential effect on methylation caused by SZ can be
determined. Furthermore, even if a SNP itself does not change the CpG the SNP may be correlated with the
methylation signal, a methylation quantitative trait locus (meQTL). Whether, the location and distribution of
these meQTLs are associated with SZ status remains to be investigated. Another type of data integration
involves datasets obtained from different study samples. If multiple data types, such as results from GWAS,
MWAS and mRNA expression analysis point towards susceptibility in specific loci, these loci are more likely to
be true findings than if they were detected by a single data type.
精神分裂症(SZ)是一种经常具有破坏性的神经精神疾病。遗传因素强烈地影响了
牵连其中。基因对SZ的贡献可能是复杂的,并超出了序列变异的范围。
DNA甲基化研究是对DNA序列分析的一个有希望的补充。因为甲基化是
与基因表达有关,例如调节元件的甲基化水平的知识可能会有所贡献
功能信息。此外,随着DNA甲基化随着时间的推移而变化,甲基化研究可以提供
洞察SZ的发病年龄和间歇性等现象。此外,它的动态性
甲基化及其对环境暴露的反应表明,甲基化可能解释了基因-
环境相互作用。
在最近的一项研究中,包括1500个SZ病例对照样本,研究了甲基组中的所有CPGS
使用基于浓缩的MBD-SEQ方法。这种方法使用了一个甲基-CpG结合域蛋白
具有高亲和力的甲基化CPGS结合下一代测序来研究
基因组中所有CPG的甲基化图谱。这些数据被用来在全基因组范围内进行
涵盖常染色体人类参考基因组中约2700万个CPG的关联研究(MWAS)。分析
SZ病例对照状态导致显著的CPGS,具有良好的生物学相关性,如缺氧和
免疫反应。结果在一个独立的研究样本中成功复制,使用High
定量亚硫酸氢盐焦磷酸测序。
目前的提案旨在对甲基组数据进行新的分析。关于表型的信息
分娩并发症(如缺氧和感染),以及抗精神病药物等处方药的使用
作为GWASSNP基因分型的基因信息,外显子组测序和外显子组芯片可从
研究样本,将在新的分析中使用。人类基因组由大量的
由SNP创建/销毁的CPG。使用MBD-SEQ方法检测这些基因的甲基化状态
CPG已经可用。然而,这些站点的分析需要一种不同于CPGS的方法
将军。通过整合甲基化和SNP信息,这些位点上的甲基化信号可以是
研究的条件是序列和SZ对甲基化的潜在影响
下定决心。此外,即使SNP本身不改变CpG,SNP也可以与
甲基化信号,甲基化数量性状基因座(MeQTL)。是否、位置和分布
这些与SZ状态相关的meQTL还有待研究。另一种类型的数据集成
涉及从不同研究样本获得的数据集。如果多种数据类型,例如来自GWA的结果,
Mwas和mRNA表达分析指向特定基因座的易感性,这些基因座更有可能
与通过单一数据类型检测到的结果相比,是真实的结果。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Karolina Anna Aberg其他文献
Karolina Anna Aberg的其他文献
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{{ truncateString('Karolina Anna Aberg', 18)}}的其他基金
Developmental methylomics of autism spectrum disorder
自闭症谱系障碍的发育甲基组学
- 批准号:
10556375 - 财政年份:2021
- 资助金额:
$ 7.63万 - 项目类别:
Developmental methylomics of autism spectrum disorder
自闭症谱系障碍的发育甲基组学
- 批准号:
10376729 - 财政年份:2021
- 资助金额:
$ 7.63万 - 项目类别:
Schizophrenia case-control study of neonatal and post onset methylomes
新生儿和发病后甲基化的精神分裂症病例对照研究
- 批准号:
9238825 - 财政年份:2017
- 资助金额:
$ 7.63万 - 项目类别:
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