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.

摘要 阿尔茨海默病(AD)和AD相关痴呆症(ADRD)的根源是发育迟缓 到生命的最早阶段。围产期的侮辱和宫内发育受限与患高血压的风险增加有关 一些AD/ADRD危险因素，包括肥胖、2型糖尿病和心脏代谢性疾病，以及 因此，它代表了AD/ADRD曝光组的一个重要特征。调节这些围产期的机制- 侮辱效应被认为是通过涉及DNA甲基化的表观遗传变化来起作用的。然而， 将宫内暴露的因果效应与相关的风险因素(如贫困)隔离开来，在 人体研究。自然实验，包括饥荒研究，提供了一个模型来研究 围产期对人类衰老的侮辱，是开发研究基础设施进行研究的理想环境 AD/ADRD曝光表。荷兰冬季饥饿家庭研究(DHWFS)使用了一种突如其来的、由战争引发的 饥荒是一种自然的实验。这场饥荒是由1944年至1945年二战期间纳粹封锁造成的。因为 饥荒的影响是直接的、短暂的和全人口范围的，DHWFS将出生的婴儿进行比较 在饥荒期间出生在饥荒之前或之后的人将确定围产期潜在的长期影响- 侮辱。在这项补充申请的父母拨款中，储存的DHWFS生物样品正在进行基因分型 研究饥荒对生育力和胎儿存活率的影响是否会在自然界引起显著的选择偏差 做实验。生物制品有N=956人可用，其中37%在宫内暴露于饥荒 其余的人是饥荒暴露者的兄弟姐妹，他们出生于 紧接在饥荒之前或之后。在这一补充申请下，我们提出了新的STORAGE分析方法 为DHWFS生成一个新的DNA甲基化数据库。我们将使用Illumina EPIC阵列 检测基因组中约850,000个CpG位点的技术；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测试数据联系起来，以 建立AD/ADRD Exposome DNA甲基化数据库；开发电子共享平台 与外部研究团队的数据。拟议的项目将为研究 AD/ADRD暴露，将能够确定宫内暴露对生命过程的影响的因果关系 通过表观遗传机制发展AD/ADRD风险。