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.

概括 阿尔茨海默病 (AD) 和 AD 相关痴呆症 (ADRD) 的根源在发育上向后延伸 生命最初阶段的围产期损伤和子宫内生长受限与风险增加有关。 多种 AD/ADRD 危险因素，包括肥胖、2 型糖尿病和心脏代谢疾病，以及 因此代表了 AD/ADRD 暴露组的一个重要特征，介导这些围产期的机制。 然而，通过涉及 DNA 甲基化的表观遗传变化来发挥作用是令人羞愧的。 将子宫内暴露的因果影响与相关风险因素（例如贫困）区分开来，在以下方面具有挑战性： 人类研究，包括饥荒研究，提供了研究因果效应的模型。 围产期对人类衰老的侮辱，是开发研究基础设施的理想环境 荷兰饥饿冬季家庭研究 (DHWFS) 使用突然的、战争引起的暴露组。 作为自然实验的饥荒 饥荒是由 1944-45 年二战期间纳粹封锁造成的。 饥荒的影响是直接的、短暂的和全人口范围的，DHWFS 对出生婴儿的比较 饥荒期间与饥荒之前或之后出生的人将确定围产期的潜在长期影响 在本补充申请的家长资助中，正在对存储的 DHWFS 生物样本进行基因分型。 研究饥荒对生育力和胎儿存活率的影响是否会在自然环境中引起显着的选择偏差 实验提供了 N=956 个人的生物样本，其中 37% 在子宫内经历过饥荒。 其余的人是遭受饥荒的人的兄弟姐妹，“时间控制者”诞生了 在饥荒之前或之后，我们提出了新的储存分析方法。 我们将使用 Illumina EPIC 阵列为 DHWFS 生成新的 DNA 甲基化数据库。 分析基因组中约 850,000 个 CpG 位点的技术，应用已发布的算法来计算文库； 暴露变量；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 暴露体 DNA 甲基化数据库；并开发电子共享平台 拟议的项目将为研究建立独特的基础设施。 AD/ADRD 暴露组将能够因果识别宫内暴露对生命历程的影响 AD/ADRD 风险通过表观遗传机制发生。