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

摘要 全球人口老龄化使延长健康寿命的干预措施成为公共卫生的优先事项。健康状况 围产期的侮辱与与衰老相关的健康状况的风险有关，包括肥胖，类型 2糖尿病和心脏代谢性疾病。如果这些关联是因果的，预防围产期出生的干预措施 侮辱和扭转其生物损害可以延缓疾病的发生并延长健康寿命。然而， 确定围产期侮辱对人类健康的长期因果影响是具有挑战性的。随机试验 是不道德的。观察性研究可能会受到混杂因素的影响，这些因素错误地表明 围产期的侮辱与后来的健康之间的联系。相比之下，自然实验可以分离出 围产期侮辱对成人疾病和健康寿命的影响。荷兰冬季饥饿家庭研究 (DHWFS)将一场突如其来的战争引发的饥荒作为一种自然实验。这场饥荒是由纳粹引起的 1944年至1945年二战期间的封锁。因为饥荒的影响是直接的，短暂的，和人口- DHWFS将饥荒期间出生的婴儿与饥荒之前或之后出生的婴儿进行广泛的比较 确定围产期侮辱的潜在长期影响。然而，饥荒自然实验研究，包括 DHWFS可能容易受到选择偏差的影响。饥荒期间出生率大幅下降；饥荒对 生育率和胎儿/婴儿存活率可能会使围产期虐待的长期影响的饥荒研究产生偏差，但这一研究尚不清楚 方式。为了填补这一知识空白，我们将对来自N=956个个体的DHWFS生物样本进行基因分型， 其中37%的人在宫内遭受饥荒，其余的人是饥荒暴露的兄弟姐妹 在饥荒之前或之后出生的个人和“时间控制者”。我们将把新的基因数据与 参与者现有的临床和认知测试以及血液DNA甲基化数据。我们将在这方面进行审查 综合多组学数据库选择性生育和胎儿/婴儿存活率的潜在影响 饥荒对(I)全基因组遗传特征；(Ii)特定衰老的多基因风险分数的差异- 相关的健康状况；以及(Iii)甲基化数量性状基因座(MQTL)基因型的差异。我们会 然后对饥荒对肥胖、2型糖尿病、认知储备和 表观遗传衰老。利用这些新资源，我们将准备一个综合的多组学数据库 DHWFS人口供外部研究小组使用，并为饥荒和 围产期侮辱研究。拟议的项目将生成一个新的知识库，以供进一步审查 可能通过遗传和衰老将围产期事件与成人健康和衰老联系起来的生物途径 表观遗传机制。

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.