Developmental methylomics of autism spectrum disorder
Developmental methylomics of autism spectrum disorder
批准号:
10376729
负责人:
Karolina Anna Aberg
金额:
$67.92万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-04-01 至 2026-01-31
关键词:
AffectAgeAlgorithmsAutopsyBindingBioconductorBiological AssayBirthBloodBlood specimenBrainBrain DiseasesCase-Control StudiesComplementDNA MethylationDNA Methylation RegulationDNA SequenceDNA analysisDataDevelopmentDiagnosisEarly DiagnosisEarly InterventionEnvironmentEnvironmental Risk FactorEpigenetic ProcessEquationEtiologyGenesGeneticGenotypeGoalsHuman GenomeIndividualInvestigationMachine LearningMediatingMethylationModelingNeonatalNeurodevelopmental DisorderParticipantPhenotypePopulationProcessProtocols documentationPsychiatryRiskRisk FactorsRoleSamplingSequence AnalysisSex BiasSiteStatistical Data InterpretationTimeUniversitiesVariantVirginiaWhole BloodX Chromosomeautism spectrum disorderbasebiobankcase controlcell typechromatin modificationdisorder riskexome sequencingexperiencefactor Afollow-upgenetic informationgenetic risk factorgenome wide association studygenome-widegenomic epidemiologyimprovedin uteromethylation biomarkermethylomemethylomicsmultidimensional datanovelphenotypic datapopulation basedprenatalrisk predictionsample collectionscreeningtranscriptome sequencingyoung adult
中文摘要
自闭症谱系障碍(ASD)是一种神经发育障碍,影响约1%的人口。
通过大规模全基因组关联来阐明ASD的遗传学方面取得了进展
研究(GWAS)和全外显子组测序(WES)研究已经确定了几个与
ASD.然而,很大一部分ASD状态不能用遗传序列变异来解释。那里
是否有多个原因可以预期DNA甲基化(DNaM)可能解释了这种未知的部分原因
变种。首先,通过DNA序列变异确定的与ASD相关的部分基因包括与
染色质修饰和dNaM。其次,自闭症可能起源于产前发育阶段,这是一段
动态调节大脑中dNaM的变化。因为这种重塑可能会导致表型突变
大脑功能失调,子宫内dNaM调节中断代表可能的自闭症风险
机制。第三,ASD与几个新生儿和其他环境风险因素有关。因为
DNaM可以被环境因素修饰,它可能介导了这些危险因素对ASD的影响。
本项目的总体目标是加深我们对dNaM在ASD病因学方面的理解,并使用dNaM
标记为ASD高危个体的早期检测。为此,我们将在整个甲基基因组范围内生成
使用18-25岁ASD病例的样本和瑞典现有病例的匹配对照的数据-
对照研究称为基于人群的自闭症遗传学和环境研究。此外,我们还将使用存储的
新生儿血液样本在出生时为这些相同的人生成第二个甲基化特征。因此,我们
将有来自所有参与者的两个时间点的血液中的甲氧基组范围的数据,伴随着
从瑞典登记处获得的从出生到当前日期的纵向表型信息。
我们将使用基于测序的方法来分析几乎所有2800万常见CpG的dNaM状态
并将执行一系列新的统计分析,包括整个甲基组
全血和血液中单个细胞类型的关联研究;结合dNaM的分析
关于新生儿危险因素的信息和已有的GWA和WES数据;以及探索其作用的研究
DNaM在ASD性别偏向中的作用。重要的发现将在四个现有的和独立的血液中重复
样本收集,并在来自ASD大脑样本的新生成的甲基化/表达数据中进行研究。
最后,我们建议使用新生儿dNaM标记来创建多标记甲基化风险评分(MRSS)
预测ASD风险。
英文摘要
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects ~1% of the population.
Progress has been made in elucidating the genetics of ASD through large-scale genome-wide association
studies (GWAS) and whole-exome sequencing (WES) studies that have identified several loci associated with
ASD. However, a substantial fraction of ASD status cannot be explained by genetic sequence variation. There
are multiple reasons to expect that DNA methylation (DNAm) may account for part of this unexplained
variation. First, part of the ASD-related genes identified via DNA sequence variation include genes involved in
chromatin modification and DNAm. Second, ASD likely originates during prenatal development, a period of
dynamically regulated changes in DNAm in the brain. As this remodeling may result in epimutations that can
dysregulate brain function, disruption of the DNAm regulation in utero represents a plausible ASD risk
mechanism. Third, ASD is associated with several neonatal and other environmental risk factors. Because
DNAm can be modified by environmental factors, it may mediate the effect of these risk factors on ASD.
The overall aims of this project is to enhance our understanding of DNAm in ASD etiology, and use DNAm
marks at for early detection of individuals at risk for ASD. For this purpose we will generate methylome-wide
data using samples from ASD cases age 18-25 years and matched controls from an existing Swedish case-
control study called Population-based Autism Genetics and Environment Study. In addition, we will use stored
neonatal blood samples to generate a second methylation profile for these same individuals at birth. Thus, we
will have methylome-wide data from blood for two time-points from all participants, accompanied by
longitudinal phenotype information spanning birth to current date obtained from the Swedish registers.
We will use a sequencing-based approach to assay the DNAm status of nearly all 28 million common CpG
sites in the human genome and will perform a battery of novel statistical analyses including methylome-wide
association studies (MWAS) of whole blood and individual cell-types in blood; analyses integrating DNAm
information with neonatal risk factors and already existing GWAS and WES data; and studies exploring the role
of DNAm in the ASD sex-bias. Significant findings will be replicated in four existing and independent blood
sample collections, and studied in the newly generated methylation/expression data from ASD brain samples.
Finally, we propose to use neonatal DNAm markers to create multi-marker methylation risk scores (MRSs) for
predicting ASD risk.
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