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: 10410379
• 负责人: Daniel Walker Belsky
• 金额: $ 51.21万
• 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/10410379
• 关键词: 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 of activation protein; Methylation; Modeling; Natural experiment; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Onset of illness; Outcome; Participant; Pathology; Pathway interactions; Perinatal; Plant Roots; Population; Prevention strategy; Process; Publishing; Quantitative Trait Loci; Research; Resources; Risk; Sampling Studies; Selection Bias; Siblings; Survivors; Testing; Time; War; Work; age related; base; cardiometabolism; cognitive reserve; cognitive testing; cohort; evidence base; 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; 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.

总结