Development of a DNA methylation data resource for exposome research on Alzheiemer's Disease and Related Dementias within the Dutch Hunger Winter Families Study

荷兰饥饿冬季家庭研究中开发用于阿尔茨海默病和相关痴呆症暴露组研究的 DNA 甲基化数据资源

• 批准号: 10661283
• 负责人: Daniel Walker Belsky
• 金额: $ 47.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661283
• 关键词: Academic Medical Centers; Address; Age; Aging; Algorithms; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Award; Biological Aging; Biological Assay; Biological Markers; Birth Rate; Birth Records; Cardiometabolic Disease; Cells; Child; Cognitive; Cohort Studies; DNA; DNA Library; DNA Methylation; Data; Databases; Dementia; Deposition; Development; Disease; Environment; Epigenetic Process; Exposure to; Family Study; Famines; Fertility; Fetal Growth Retardation; Follow-Up Studies; Food Supply; Future; Genome; Genotype; Health; Hospitals; Human; Hunger; Immune; Individual; Infant; Infrastructure; Libraries; Life; Life Cycle Stages; Link; Long-Term Effects; Measurement; Measures; Mediating; Modeling; Natural experiment; Neurocognitive; Neuropsychological Tests; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Participant; Pathway interactions; Perinatal; Plant Roots; Population; Poverty; Pregnancy; Proteins; Publishing; Quality Control; Research; Research Infrastructure; Research Personnel; Risk; Risk Factors; Role; SNP genotyping; Sampling; Sampling Studies; Selection Bias; Siblings; Site; Survivors; Technology; Testing; Time; Toxic Environmental Substances; Toxicant exposure; Universities; Update; War; Whole Blood; base; biobank; biomarker development; biomarker evaluation; cardiometabolic risk; cardiometabolism; cohort; course development; data quality; data resource; data sharing; dementia risk; electronic data sharing; fetal; follow-up; genetic analysis; health disparity; in utero; member; methylation biomarker; middle age; multiple omics; next generation; parent grant; parent project; performance tests; prenatal exposure; response; virtual; web services; whole genome

SUMMARY The roots of Alzheimer’s Disease (AD) and AD-Related Dementias (ADRD) extend backward in development to the earliest stages of life. Perinatal insults and intra-uterine growth restriction are linked to increased risk for several AD/ADRD risk factors, including obesity, type 2 diabetes mellitus, and cardio-metabolic disease, and therefore represent a crucial feature of the AD/ADRD exposome. The mechanisms mediating these perinatal- insult effects are hypothesized to operate through epigenetic changes involving DNA methylation. However, isolating the causal effects of in-utero exposures from correlated risk factors, such as poverty, is challenging in human studies. Natural experiments, including famine studies, provide a model to study causal effects of perinatal insults on human aging and are an ideal setting in which to develop research infrastructure to study the AD/ADRD exposome. The Dutch Hunger Winter Families Study (DHWFS) uses a sudden, war-induced famine as a natural experiment. The famine was caused by a Nazi blockade during WWII in 1944-45. Because the impact of famine was immediate, transient, and population-wide, DHWFS comparison of infants born during the famine with those born before or after the famine will identify potential long-term effects of perinatal- insults. In the parent grant to this supplement application, stored DHWFS biospecimens are being genotyped to examine if famine effects on fertility and fetal survival could induce significant selection bias in the natural experiment. Biospecimens are available of N=956 individuals, 37% of whom were exposed to famine in-utero and the remainder of whom are siblings of the famine-exposed individuals and "time controls" born immediately before or after the famine. Under this supplement application we propose new assays of stored biospecimens to generate a new DNA methylation database for the DHWFS. We will use Illumina EPIC array technology to assay ~850,000 CpG sites across the genome; apply published algorithms to compute a library of exposome variables; link these data with detailed in-utero exposure and neuropsychological test data to build an AD/ADRD exposome DNA methylation database; and develop platforms for electronic sharing of the data with outside research teams. The proposed project will build unique infrastructure for studies of the AD/ADRD exposome that will enable causal identification of impacts of in-utero exposure on the life-course development of AD/ADRD risk via epigenetic mechanisms.

总结 阿尔茨海默病（AD）和AD相关痴呆（ADRD）的根源在发育过程中向后延伸 到生命的最初阶段。围产期损伤和宫内生长受限与以下风险增加有关： 几种AD/ADRD风险因素，包括肥胖、2型糖尿病和心脏代谢疾病，以及 因此代表AD/ADRD疾病组的关键特征。调节这些围产期- 假设损伤效应通过涉及DNA甲基化的表观遗传变化起作用。然而，在这方面， 将宫内暴露的因果影响与相关风险因素（如贫困）分离开来， 人类研究自然实验，包括饥荒研究，提供了一个模型，研究因果关系的影响， 围产期对人类衰老的影响，是发展研究基础设施的理想环境， AD/ADRD麻烦。荷兰饥饿冬季家庭研究（DHWFS）使用了一个突然的，战争引起的 饥荒是一个自然实验。饥荒是由1944 - 45年二战期间纳粹封锁造成的。因为 饥荒的影响是直接的、短暂的，而且是全人口范围的。 在饥荒期间与那些在饥荒之前或之后出生的人将确定围产期的潜在长期影响- 侮辱。在本补充申请的母基金中，储存的DHWFS生物标本正在进行基因分型 研究饥荒对生育力和胎儿存活的影响是否会在自然界中引起显著的选择偏差， 实验可获得N = 956个个体的生物标本，其中37%在子宫内暴露于饥荒 其余的人是饥荒暴露个体的兄弟姐妹， 在饥荒之前或之后。在该补充申请中，我们提出了新的储存的 生物标本生成一个新的DHWFS的DNA甲基化数据库。我们将使用Illumina EPIC阵列 该技术可测定基因组中约850，000个CpG位点;应用已发表的算法计算文库 将这些数据与详细的宫内暴露和神经心理学测试数据联系起来， 建立AD/ADRD基因组DNA甲基化数据库，并开发电子共享平台， 与外部研究团队一起收集数据。拟议的项目将为研究建立独特的基础设施 能够确定宫内暴露对生命过程影响的因果关系的AD/ADRD基因组 通过表观遗传机制发展AD/ADRD风险。