Random Field Modelling of genetic and epigenetic association underlying congenital heart defects in the presence of disease heterogeneity

存在疾病异质性的情况下先天性心脏缺陷的遗​​传和表观遗传关联的随机场建模

• 批准号: 10405321
• 负责人: Ming Li
• 金额: $ 5.03万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-01-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405321
• 关键词: Area; Biological; Biostatistical Methods; COVID-19; COVID-19 pandemic; Cardiovascular Diseases; Congenital Abnormality; Congenital Heart Defects; Counseling; Data Sources; Disease; Epidemiologist; Epigenetic Process; Etiology; Foundations; Future; Genetic; Genetic Models; Genetic Transcription; Goals; Institution; Interruption; Intervention; Journals; Life Style; Mentored Research Scientist Development Award; Methods; National Heart, Lung, and Blood Institute; National Institute of Child Health and Human Development; Pathway interactions; Pediatric Cardiac Genomics Consortium; Peer Review; Population Study; Prevention; Principal Investigator; Process; Publications; Publishing; Research; Risk; Risk Factors; Sampling; Site; Time; Trans-Omics for Precision Medicine; Translational Research; United States National Institutes of Health; attributable mortality; base; career; disease heterogeneity; experience; infant morbidity/mortality; innovation; insight; interest; lifestyle factors; personalized intervention; predictive modeling; symposium

Project Summary/Abstract This proposal is submitted for an extension of the NHLBI K01 award, entitled “Random field modeling of genetic and epigenetic associations for congenital heart defects in the presence of disease heterogeneity”. Dr. Ming Li is the principal investigator of this study, and is within the final year of this K01 award (01/01/2018 – 12/31/2021). In the past year, Dr. Li’s research team has experienced substantial research interruptions and additional administrative responsibilities due to the COVID-19 pandemic. This extension is expected to provide Dr. Li the necessary time to complete the ongoing K01 projects and to make successfully transition to future R01 studies. Dr. Li’s career goal is to become an independent statistical geneticist and genetic epidemiologist in cardiovascular diseases, particularly in congenital heart defects (CHDs). In the past three years, Dr. Li has been developing innovative biostatistical methods for detecting genetic and epigenetic factors associated with the risk of CHDs. The proposed methods are being applied to samples from the National Birth Defect Prevention Study (NBDPS), the largest multi-site population-based study of birth defects ever conducted. So far, substantial progresses have been made with a number of key findings published in peer-review journals. Additional findings were also presented at the major conferences and submitted for publications, but also experienced delays largely due to COVID-19 interruptions. These results have provided insights into the underlying pathophysiological and etiological processes that result in CHDs, and will also serve as a foundation for Dr. Li to make propose additional R01 studies. The future R01 studies will mainly be focused on two aspects: 1) to apply the newly developed biostatical methods to other existing NHLBI data sources, such as the Pediatric Cardiac Genomics Consortium (PCGC) and Trans-Omics for Precision Medicine (TOPMed); and 2) to further develop innovative biostatistical methods for disease prediction and precision intervention based on the genetic, epigenetic, transcriptional and maternal lifestyle profiles. The continuation of this research will integrate data sources across NIH institutions (i.e. NICHD and NHLBI), and also may provide a direction for translational research leading to more precise preconceptional counseling and interventions. Such research directions are also consistent with NHLBI’s emphasized research areas as described in multiple notices of special interests (e.g. NOT-HL-20-815).

项目概要/摘要 该提案是为了延长 NHLBI K01 奖而提交，题为“遗传的随机场建模” 以及存在疾病异质性的先天性心脏缺陷的表观遗传关联”。 是这项研究的主要研究者，并且处于 K01 奖项的最后一年（2018 年 1 月 1 日 – 2021 年 12 月 31 日）。 在过去的一年里，李博士的研究团队经历了大幅的研究中断和额外的研究。 此次延期预计将为李博士提供因 COVID-19 大流行而承担的行政责任。 完成正在进行的 K01 项目并成功过渡到未来的 R01 研究所需的时间。 李博士的职业目标是成为一名独立的统计遗传学家和遗传流行病学家。 过去三年，李医生一直致力于心血管疾病，特别是先天性心脏病（CHD）的治疗。 开发创新的生物统计方法来检测与风险相关的遗传和表观遗传因素 所提出的方法正应用于国家出生缺陷预防研究的样本。 （NBDPS），迄今为止进行的最大规模的基于人群的出生缺陷研究。 同行评审期刊上发表了一些重要发现，取得了进展。 也在主要会议上提出并提交出版，但也经历了很大程度上的延误 由于 COVID-19 的干扰，这些结果提供了对潜在病理生理学和病理学的见解。 导致冠心病的病因学过程，也将作为李博士提出其他建议的基础 R01的研究。未来R01的研究将主要集中在两个方面：1）应用新开发的技术。 其他现有 NHLBI 数据源（例如儿科心脏基因组学联盟）的生物静态方法 (PCGC) 和 Trans-Omics for Precision Medicine (TOPMed)；2) 进一步开发创新的生物统计 基于遗传、表观遗传、转录因子等的疾病预测和精准干预方法 这项研究的继续将整合 NIH 机构的数据源。 （即 NICHD 和 NHLBI），也可能为转化研究提供方向，从而实现更精确的结果 此类研究方向也与 NHLBI 一致。 强调多个特殊兴趣通知中描述的研究领域（例如 NOT-HL-20-815）。

项目成果

A gene-based association test of interactions for maternal-fetal genotypes identifies genes associated with nonsyndromic congenital heart defects.

基于基因的母胎基因型相互作用关联测试可识别与非综合征性先天性心脏病相关的基因。

• 发表时间: 2023-10
• 影响因子: 2.1
• 作者: Huang, Manyan;Lyu, Chen;Liu, Nianjun;Nembhard, Wendy N;Witte, John S;Hobbs, Charlotte A;Li, Ming;National Birth Defects Prevention Study
• 通讯作者: National Birth Defects Prevention Study

Mapping methylation quantitative trait loci in cardiac tissues nominates risk loci and biological pathways in congenital heart disease.

绘制心脏组织中的甲基化数量性状位点可以指定先天性心脏病的风险位点和生物学途径。

• 发表时间: 2021
• 影响因子: 1.9
• 作者: Li, Ming;Lyu, Chen;Huang, Manyan;Do, Catherine;Tycko, Benjamin;Lupo, Philip J;MacLeod, Stewart L;Randolph, Christopher E;Liu, Nianjun;Witte, John S;Hobbs, Charlotte A
• 通讯作者: Hobbs, Charlotte A

Detecting methylation quantitative trait loci using a methylation random field method.

使用甲基化随机场方法检测甲基化数量性状位点。

• 发表时间: 2021-11-05
• 影响因子: 9.5
• 作者: Lyu, Chen;Huang, Manyan;Liu, Nianjun;Chen, Zhongxue;Lupo, Philip J;Tycko, Benjamin;Witte, John S;Hobbs, Charlotte A;Li, Ming
• 通讯作者: Li, Ming

Identifying Susceptibility Loci for Cutaneous Squamous Cell Carcinoma Using a Fast Sequence Kernel Association Test.

使用快速序列核关联测试识别皮肤鳞状细胞癌的易感性位点。

• 发表时间: 2021
• 作者: Huang, Manyan;Lyu, Chen;Li, Xin;Qureshi, Abrar A;Han, Jiali;Li, Ming
• 通讯作者: Li, Ming

Random field modeling of multi-trait multi-locus association for detecting methylation quantitative trait loci.

用于检测甲基化数量性状基因座的多性状多基因座关联的随机场建模。

• 发表时间: 2022-08-10
• 作者: Lyu, Chen;Huang, Manyan;Liu, Nianjun;Chen, Zhongxue;Lupo, Philip J;Tycko, Benjamin;Witte, John S;Hobbs, Charlotte A;Li, Ming
• 通讯作者: Li, Ming