Genetic analysis of the Dutch Hunger Winter Families Study to Boost Rigor and Robustness for Testing In-Utero Famine Effects on Aging-Related Health Conditions and Biological Aging

荷兰饥饿冬季家庭研究的遗传分析，以提高测试宫内饥荒对衰老相关健康状况和生物衰老影响的严谨性和稳健性

• 批准号: 10626012
• 负责人: Daniel Walker Belsky
• 金额: $ 51.51万
• 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/10626012
• 关键词: Acceleration; Accounting; Address; Adult; Affect; Age; Aging; Animal Experiments; Biological; Biological Aging; Biological Assay; Birth; Birth Rate; Blood; Blood specimen; Cardiometabolic Disease; Characteristics; Child; Chronic Disease; Clinical; Cognitive; Conceptions; DNA Methylation; DNA Sequence; Data; Databases; Development; Disease; Elderly; Epigenetic Process; Event; Exposure to; Family Study; Famines; Fertility; Fetal Growth Retardation; Fetal Mortality Statistics; Future; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health; Human; Hunger; Individual; Infant; Intervention; Knowledge; Life; Life Cycle Stages; Link; Long-Term Effects; Longevity; Measures; Mediator; Methylation; Modeling; Natural experiment; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Onset of illness; Outcome; Participant; Pathology; Pathway interactions; Perinatal; Population; Prevention strategy; Process; Publishing; Quantitative Trait Loci; Research; Resources; Risk; Sampling Studies; Selection Bias; Siblings; Survivors; Testing; Time; War; Work; age related; cardiometabolism; cognitive reserve; cognitive testing; cohort; evidence base; experimental study; fetal; follow-up; genetic analysis; genetic approach; genetic information; genetic selection; genetic testing; genetic variant; genome wide association study; genome-wide; healthspan; improved; in utero; knowledge base; member; multiple omics; novel strategies; perinatal period; polygenic risk score; prenatal; prevent; public health priorities; randomized trial; study population; treatment strategy; unethical; whole genome

SUMMARY The graying global population makes interventions to extend healthy lifespan a public heath priority. Health insults during the perinatal period are linked with risk for aging-related health conditions, including obesity, type 2 diabetes, and cardio-metabolic disease. If these associations are causal, interventions to prevent perinatal insults and to reverse their biological damage could delay disease onset and prolong healthspan. However, establishing causal long-term health effects of perinatal insults in humans is challenging. Randomized trials would be unethical. Observational studies can be biased by confounding factors that erroneously suggest a link between insults in the perinatal period and later health. In contrast, natural experiments can isolate the impact of perinatal insults on adult disease and healthspan. 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. However, famine natural-experiment studies, including DHWFS, may be vulnerable to selection bias. Birth rates decline significantly during famine; famine’s impact on fertility and fetal/infant survival might bias famine studies of perinatal insult’s long-term effects in unknown ways. To fill this gap in knowledge, we will genotype stored DHWFS biospecimens from 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. We will link new genetic data with participants’ existing clinical and cognitive tests and blood DNA methylation data. We will examine in this integrative multi-omics database the potential impact of selective fertility and fetal/infant survival during the famine on (i) genome wide genetic characteristics; (ii) differences in polygenic risk scores for specific aging- related health conditions; and (iii) differences in methylation quantitative trait loci (mQTL) genotypes. We will then conduct genetics-informed analysis of famine effects on obesity, type-2 diabetes, cognitive reserve, and epigenetic aging. Using these new resources, we will prepare an integrated multi-omics database of the DHWFS population for use by outside research teams and generate a one of a kind resource for famine and perinatal insult research. The proposed project will generate a new knowledge base to further examine biological pathways that are likely to connect perinatal events to adult health and aging through genetic and epigenetic mechanisms.

概括 灰色的全球人口使延长健康寿命的干预措施是公共荒地的优先事项。健康 围产期期间的侮辱与衰老相关的健康状况的风险有关，包括肥胖，类型 2种糖尿病和心脏代谢疾病。如果这些关联是因果关系，请采取干预措施以防止围产期 侮辱并扭转其生物损害可能会延迟疾病发作并延长健康状况。然而， 建立人类围产期伤害的因果关系长期健康影响是具有挑战性的。随机试验 将是不道德的。观察性研究可能会被混杂因素偏见，这些因素错误地表明 在围产期时期与以后的健康之间的侮辱之间的联系。相反，自然实验可以隔离 围产期损伤对成人疾病和健康状态的影响。荷兰饥饿冬季家庭研究 （DHWFS）将突然的战争引起的饥荒作为自然实验。饥荒是由纳粹造成的 1944 - 45年第二次世界大战期间的封锁。因为饥荒的影响是直接，短暂和人口的影响 广泛的DHWF在饥荒期间出生的婴儿与饥荒之前或之后出生的婴儿的比较 确定围产期侵袭的潜在长期影响。但是，饥荒的自然体验研究，包括 DHWFS，可能容易受到选择偏见的影响。饥荒期间的出生率显着下降；饥荒对 生育能力和胎儿/婴儿的生存可能会偏向于围产期感染对未知的长期影响的饥荒研究 方式。为了填补这一知识的空白，我们将基因型存储的DHWFS生物测量来自n = 956个个体， 37％的人暴露于Utero中的饥荒，其余的是暴露于饥荒的兄弟姐妹 个人和“时间控制”在饥荒之前或之后出生。我们将将新的遗传数据与 参与者的现有临床和认知测试以及血液DNA甲基化数据。我们将在此研究 综合多矩数据库选择性生育能力和胎儿/婴儿存活期间的潜在影响 （i）基因组广泛遗传特征的饥荒； （ii）特定衰老的多基因风险评分差异 - 相关的健康状况； （iii）甲基化定量性状基因座（MQTL）基因型的差异。我们将 然后对饥荒对肥胖，2型糖尿病，认知储备和 表观遗传衰老。使用这些新资源，我们将准备一个集成的多摩尼斯数据库 DHWFS人口供外部研究团队使用，并为饥荒和 围产期侮辱研究。拟议的项目将产生一个新的知识基础，以进一步检查 可能将围产期事件与成人健康和通过遗传和衰老相关的生物途径 表观遗传机制。