Random Field Modelling of Genetic and Epigenetic Association for Congenital Heart Defects in the Presence of Disease Heterogeneity

项目概要/摘要 这项指导研究科学家发展奖的提案旨在为候选人提供 成为一名独立的统计遗传学家和遗传流行病学家所需的时间和资源 心血管疾病，特别是先天性心脏病（CHD）。这一目标将通过以下方式实现 增强培训和研究经验：1）通过参加出生缺陷相关领域的教学课程 流行病学、生殖遗传学和综合基因组学方法； 2）通过实施研究 先心病基因组和表观基因组研究项目； 3) 组建一个由导师组成的专家小组 广泛且互补的技能。拟议的 K01 计划将补充候选人之前的计划 接受统计学、流行病学和定量生物学方面的培训，优化他的努力以完成拟议的研究 项目，并让他成为一名独立调查员。 （共同）导师，博士。刘念君和约翰·S. Witte 将为候选人在综合基因组学方法领域的培训提供建议。 （共同）导师， 博士。 Charlotte A. Hobbs、Benjamin Tycko 和 Jiali Han 将为候选人的出生领域培训提供建议 遗传学、流行病学和生殖遗传学。在拟议的项目中，创新的生物统计方法 将开发并应用于国家出生缺陷预防研究 (NBDPS) 的样本，这是最大的 曾经进行过以人口为基础的多地点出生缺陷研究。我们将利用基因组数据（即约 500 万 约 1,000 个案例母-父-婴三联体和约 1,000 个对照母-婴二联体，以及 71 个心脏组织样本的表观遗传数据（即约 450K 甲基化位点）。拟议的项目将解决 先心病研究面临的三大挑战：1）先心病的遗传异质性，即“幸福的家庭都是相似的” 每个不幸的家庭都有自己的不幸”； 2）特定组织内遗传变异的功能影响， 例如遗传变异和表观遗传修饰之间的关联； 3）复杂的相互作用 潜在的先心病，包括遗传变异、表观遗传修饰和 产妇生活方式因素。候选人已成功完成两年的 KL2 辅导职业 发展奖，题为“检测与基因相关的基因间和基因间环境相互作用” CHD”，这为我们将建立更详细的研究来解决拟议的问题奠定了基础 主题。这些发现可能有助于深入了解潜在的病理生理学和病因学过程 导致先心病，更重要的是，可以为转化研究提供方向，从而导致更多 精准的孕前咨询和干预。从培训和研究中获得的经验 拟议的研究将作为独立研究计划的基础，包括新的 R01 提案 扩展将通过拟议的 K01 计划启动的研究。

Project Summary/Abstract This proposal for a Mentored Research Scientist Development Award is designed to provide the candidate the necessary time and resources to transit into an independent statistical geneticist and genetic epidemiologist in cardiovascular diseases, particularly in congenital heart defects (CHDs). This goal will be achieved through enhanced training and research experience: 1) by taking didactic courses in areas related to birth defects epidemiology, reproductive genetics and integrative genomics methodologies; 2) by implementing research projects for genomic and epigenomic studies of CHDs; and 3) by assembling an expert panel of mentors with extensive and complementary skills. The proposed K01 program will complement the candidate's previous training in statistics, epidemiology and quantitative biology, optimize his effort to complete the proposed research projects, and allow him to become an independent investigator. The (co-)mentors, Drs. Nianjun Liu and John S. Witte, will advise the candidate's training in the domain of integrative genomics methodologies. The (co-)mentors, Drs. Charlotte A. Hobbs, Benjamin Tycko and Jiali Han will advise the candidate's training in the domain of birth genetics epidemiology and reproductive genetics. In the proposed projects, innovative biostatistical approaches will be developed and applied to samples from the National Birth Defect Prevention Study (NBDPS), the largest multi-site population-based study of birth defects ever conducted. We will utilize the genomic data (i.e. ~ 5 million genetic variants) of ~ 1,000 case mother-father-infant triads and ~ 1,000 control mother-infant dyads, and the epigenetic data (i.e. ~ 450K methylation sites) of 71 cardiac tissue samples. The proposed projects will address three challenges in CHD research: 1) the genetic heterogeneity of CHDs, known as “all happy families are alike, each unhappy family is unhappy in its own way”; 2) the functional effects of genetic variants within specific tissues, such as the association between genetic variations and epigenetic modifications; and 3) the complex interactions underlying CHDs, including the high-order interactions among genetic variants, epigenetic modifications and maternal life style factors. The candidate has successfully completed a two-year KL2 Mentored Career Development Award, entitled “detecting gene-by-gene and gene-by-environment interactions associated with CHDs”, which provides a foundation onto which we will build more detailed studies to address the proposed topics. The findings will likely provide insights into the underlying pathophysiological and etiological processes that result in CHDs, and more importantly, can provide a direction for translational research leading to more precise preconceptional counseling and interventions. The training and research experience gained from the proposed study will serve as the groundwork for an independent research program, including a new R01 proposal to expand upon the research that will be initiated through this proposed K01 program.