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 阿尔茨海默氏病（AD）和与广告相关的痴呆症（ADRD）的根源向后扩展 到生命的最早阶段。围产期侮辱和核内生长限制与增加的风险有关 几种AD/ADRD风险因素，包括肥胖，2型糖尿病和心甲状代谢疾病，以及 因此，代表了AD/ADRD展示体的关键特征。介导这些围产期的机制 假设侮辱作用是通过涉及DNA甲基化的表观遗传变化来运作的。然而， 隔离诸如贫困等相关风险因素（例如贫困）的UTERO暴露的因果影响是挑战 人类研究。自然实验（包括饥荒研究）提供了研究的模型来研究 围产期侮辱人类衰老，是开发研究基础设施以研究的理想环境 广告/ADRD展示体。荷兰饥饿冬季家庭研究（DHWFS）使用突然的战争引起的 饥荒作为自然实验。饥荒是由1944 - 45年第二次世界大战期间的纳粹封锁造成的。因为 饥荒的影响是直接的，短暂的和人口范围的，DHWF的婴儿比较 在饥荒的饥荒期间，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。在此补充剂应用程序的父授予中，正在基因分型储存的DHWFS生物测量 检查饥荒对生育和胎儿存活的影响是否会引起自然的重大选择偏见 实验。 n = 956个人可获得生物测量，其中有37％暴露于饥荒中 其余的是暴露于饥荒的人的兄弟姐妹，并且“时间控制”出生 饥荒之前或之后。在此补充申请下，我们提出了存储的新测定 生物测量为DHWF生成新的DNA甲基化数据库。我们将使用Illumina Epic Array 在整个基因组中测定约85万CPG站点的技术；应用已发布的算法来计算库 暴露变量；将这些数据与详细的UTERO内暴露和神经心理学测试数据联系起来 构建AD/ADRD释放DNA甲基化数据库；并开发用于电子共享的平台 与外部研究团队的数据。拟议的项目将建立独特的基础设施，以研究 AD/ADRD暴露将使因子情况对生命过程的影响能力识别 通过表观遗传机制开发AD/ADRD风险。