Developmental methylomics of autism spectrum disorder

自闭症谱系障碍的发育甲基组学

• 批准号: 10556375
• 负责人: Karolina Anna Aberg
• 金额: $ 66.8万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556375
• 关键词: Affect; Age; Algorithms; Autopsy; Binding; Bioconductor; Biological Assay; Birth; Blood; Blood specimen; Brain; Brain Diseases; Case/Control Studies; Complement; DNA Integration; DNA Methylation; DNA Methylation Regulation; DNA Sequence; DNA analysis; Data; Development; Diagnosis; Early Diagnosis; Early Intervention; Environment; Environmental Risk Factor; Epidemiology; Epigenetic Process; Equation; Etiology; Genes; Genetic; Genomics; Genotype; Goals; Human Genome; Individual; Investigation; Machine Learning; Mediating; Methylation; Modeling; Neonatal; Neurodevelopmental Disorder; Participant; Phenotype; Population; Process; Protocols documentation; Psychiatry; Risk; Risk Factors; Role; Sampling; Sequence Analysis; Sex Bias; Site; Statistical Data Interpretation; Time; Universities; Variant; Virginia; Whole Blood; X Chromosome; autism spectrum disorder; biobank; cell type; chromatin modification; disorder risk; exome sequencing; experience; factor A; follow-up; genetic information; genetic risk factor; genome wide association study; genome-wide; improved; in utero; methylation biomarker; methylome; methylomics; multidimensional data; novel; phenotypic data; population based; prenatal; risk prediction; sample collection; screening; transcriptome sequencing; young adult

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.

自闭症谱系障碍（ASD）是一种神经发育障碍，影响约1%的人口。 通过大规模的全基因组关联，在阐明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，已经确定了与 自闭症然而，ASD状态的很大一部分不能用遗传序列变异来解释。那里 有多种理由认为DNA甲基化（DNAm）可能是导致这一无法解释的原因之一。 变化量首先，通过DNA序列变异鉴定的部分ASD相关基因包括涉及以下的基因： 染色质修饰和DNAm。其次，ASD可能起源于产前发育， 动态调节大脑中DNA的变化。由于这种重塑可能导致表突变， 脑功能失调，子宫内DNAm调节的破坏代表了ASD的合理风险 机制第三，ASD与几个新生儿和其他环境风险因素有关。因为 环境因素可以改变DNA m，它可能介导这些危险因素对ASD的影响。 本项目的总体目标是提高我们对DNA m在ASD病因学中的理解， 标志着早期发现个体的ASD风险。为此，我们将产生全甲基化 数据使用来自18-25岁ASD病例的样本和来自现有瑞典病例的匹配对照， 一项名为“基于人群的自闭症遗传学和环境研究”的对照研究。此外，我们将使用存储 新生儿血液样本，以产生这些相同个体在出生时的第二甲基化谱。因此我们 将从所有参与者的血液中获得两个时间点的全甲基化组数据， 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2800万个常见CpG的DNAm状态 在人类基因组中的位点，并将进行一系列新的统计分析，包括甲基化全 全血和血液中单个细胞类型的关联研究（MWAS）;整合DNAm的分析 新生儿风险因素的信息和现有的GWAS和WES数据;以及探索作用的研究 ASD性别偏见中的DNA重要的发现将在四个现有的和独立的血液 样品收集，并在来自ASD脑样品的新生成的甲基化/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（MRS）， 预测ASD风险。