Host genetics, early-life microbiome, and childhood asthma: MARC-43 Boston

项目摘要 最近的研究报告了早期微生物组与各种儿童健康之间的概率关联 结果（例如，肥胖，哮喘），这表明对发病机制和随后的，有针对性的 制定预防措施。然而，早期微生物组对儿童健康的因果作用 仍不清楚。我们的初步工作应用了最先进的统计遗传学和因果推理 在我们的ECHO支持的队列中，采用大型遗传学和微生物组数据的方法，证明：1）宿主 不同种族/民族人群中气道链球菌的遗传基因座，2）肠道微生物组的宿主遗传基因座 并显著富集生物途径（例如，神经元发育调控，葡萄糖醛酸 相互转化），以及3）肠道拟杆菌与肥胖和哮喘风险的关系。我们的核心假设 基因驱动的肠道和上呼吸道微生物组在生命的头两年中具有因果作用， 儿童健康结果的发展，如肥胖和气道结果。UG 3/UH 3项目将 通过应用最新的统计遗传学和流行病学方法来测试这一创新假设，例如， 微生物组全基因组关联研究（mGWAS）-大型ECHO遗传学，微生物组和广泛的 临床和环境数据。通过使用ECHO核心数据元素，Aim 1将生成mGWAS摘要 统计数据，使研究人员能够检查早期微生物组对儿童健康的因果作用 结果。例如，通过使用mGWAS和孟德尔随机化方法，我们将确定 肠道和鼻气道微生物组（0-1.9岁期间）在发生以下疾病风险中的因果作用： 儿童肥胖症通过使用专门的气道结果数据，Aim 2将确定是否遗传性 驱动的肠道和鼻腔微生物组对哮喘的发展（及其主要表型）具有因果作用 以及儿童后期肺功能下降。目标3将最大限度地保留现有的ECHO队列 协议（ECP）的参与者，强调多样性，并以高保真度实施ECP。(To于上述各各 MARC-43波士顿参与者，ECP保留率为100%，数据完整性>80%。）拟建项目 将作为一个国家研究资源，用于研究早期生命微生物组在各种疾病中的因果作用。 儿童健康成果。此外，该项目将为今后提供一个强有力的证据基础 制定有针对性的微生物组干预措施，以预防儿童肥胖和哮喘。调查人员 是NIH资助的研究人员，在所有相关领域具有国际专业知识（例如，流行病学、统计学 遗传学、微生物组、儿童肥胖症、哮喘）。该项目与欧共体人道处的目标非常吻合 程序.

Project Abstract Recent studies report probabilistic associations between the early-life microbiome and various child health outcomes (e.g., obesity, asthma), suggesting potential insights into pathogenesis and subsequent, targeted development of preventive interventions. However, the causal role of the early-life microbiome on child health remains unclear. Our preliminary work has applied state-of-art statistical genetics and causal inference approaches to large genetics and microbiome data in our ECHO-supported cohorts, demonstrating: 1) host genetic loci for airway Streptococcus across racial/ethnic populations, 2) host genetic loci for gut microbiome and significantly enriched biological pathways (e.g., regulation of neuron development, glucuronate interconversions), and 3) relationship of gut Bacteroides with obesity and asthma risk. Our central hypothesis is that the genetically driven gut and upper airway microbiome in the first two years of life has a causal role in the development of child health outcomes, such as obesity and airway outcomes. This UG3/UH3 project will test this innovative hypothesis by applying the latest statistical genetics and epidemiological methods—e.g., microbiome genome-wide association study (mGWAS)— to large ECHO genetics, microbiome, and extensive clinical and environmental data. By using ECHO core data elements, Aim 1 will generate mGWAS summary statistics to enable researchers to examine the causal role of the early-life microbiome on child health outcomes. For example, by using the mGWAS and Mendelian randomization approaches, we will determine the causal role of the gut and nasal airway microbiome (during age 0-1.9 years) in the risk of developing childhood obesity. By using specialized airway outcome data, Aim 2 will determine whether the genetically driven gut and nasal microbiome has a causal effect on the development of asthma (and its major phenotypes) and on lower lung function in later childhood. Aim 3 will maximize the retention of existing ECHO Cohort Protocol (ECP) participants, with emphasis on diversity, and implement the ECP with high fidelity. (To date, in MARC-43 Boston participants, ECP retention is 100%, with >80% data completeness.) The proposed project will serve as a national research resource for examining the causal role of early-life microbiome in various childhood health outcomes. Furthermore, the project will provide a robust evidence base for the future development of targeted microbiome interventions to prevent childhood obesity and asthma. The investigators are NIH-funded researchers with international expertise in all relevant fields (e.g., epidemiology, statistical genetics, microbiome, childhood obesity, asthma). The project matches well with the goals of the ECHO Program.