A Twin Approach for Genome-Wide Differential DNA Methylation in Orofacial Clefting

口颌面裂中全基因组差异 DNA 甲基化的双重方法

• 批准号: 9980356
• 负责人: Aline L Petrin
• 金额: $ 13.92万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980356
• 关键词: Aberrant DNA Methylation; Affect; Area; Behavioral; Big Data; Biological; Caring; Cleft Lip; Cleft Palate; Complex; Congenital Abnormality; Cytosine Nucleotides; DNA; DNA Methylation; DNA Sequence; DNA sequencing; Data; Data Set; Dental; Development; Disease; Environmental Risk Factor; Epigenetic Process; Etiology; Foundations; Funding Opportunities; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Genotype; Goals; Growth; Healthcare Systems; Heritability; Human; Individual; Interdisciplinary Study; Knowledge; Lead; Life; Mediating; Mental disorders; Mentors; Methods; Methylation; Minority; Modification; Monozygotic twins; Nutritional; Operative Surgical Procedures; Patients; Phenotype; Play; Positioning Attribute; Prevention; Quality of life; Quantitative Trait Loci; Research; Research Personnel; Research Training; Resources; Risk; Risk Estimate; Risk Factors; Role; Sampling; Siblings; Single Nucleotide Polymorphism; Site; Societies; Speech; Suicide; Susceptibility Gene; Testing; Therapeutic; Tissue-Specific Gene Expression; Training; Twin Multiple Birth; Variant; Work; analytical method; base; bead chip; cancer type; career; case control; cleft lip and palate; cohort; cost; craniofacial; craniofacial complex; design; digital; ear infection; epigenetic regulation; experience; feeding; genetic risk factor; genetic variant; genome wide association study; genome wide methylation; genome-wide; genome-wide analysis; genome-wide linkage; innovation; methylation pattern; mortality; novel; orofacial cleft; psychosocial; risk variant

Abstract Nonsyndromic orofacial clefts (OFCs) are the most common craniofacial birth defects in humans, affecting approximately 1 in 700 individuals worldwide. Genome-wide linkage and association studies have identified several risk alleles for OFCs; however, they account for a minority of their estimated heritability. Therefore, while the ongoing genetic and expression studies may lead to important advances in understanding the biological basis underlying OFCs, a fuller picture will only emerge as the interaction of susceptibility variants with other factors, such as epigenetic changes, are established. Epigenetic modification is a likely mechanism through which environmental factors and genetic variation may alter gene expression. DNAm is a covalent addition of a methyl (CH3) group to the nucleotide cytosine, which can lead to changes in transcriptional activity of the targeted gene. We hypothesize that changes in methylation and the resulting differential gene expression is an epigenetic risk factor for OFCs, and that DNAm mediates genetic influences in OFCs risk. Our main goals are to characterize genome-wide DNAm variation that can impact the risk for OFCs; and explore the genetic-epigenetic interactions (meQTLs) involved in the etiology of OFC. To do so, this project proposes a powerful strategy using the largest sample set (to date) of monozygotic twins and sibling pairs discordant for nonsyndromic OFCs used to study epigenetic risk factors. This is a key step and an innovative approach that will allow uncovering epigenetics risk factors that are invisible to conventional GWAS and DNA sequencing methods. The central hypothesis of this proposal will be tested with the following specific aims: (1) To determine genome-wide DNA methylation patterns in MZ twins discordant for OFCs; (2) To explore the genetic-epigenetic interactions (meQTLs) involved in the etiology of OFCs. Within aim 2 we will attempt to replicate the genetic-epigenetic interactions identified in the preliminary analysis (obtained since the first submission of this proposal), and top hits resulting from Aim 1, using an independent cohort of cleft discordant sibling pairs. The outstanding team of mentors (Dr. Jeff Murray, Dr. Robert Philibert, Dr. Mary Marazita, and Dr. Moreno-Uribe), consultants (Dr. Xie, and Dr. Drake), collaborator (Dr. Lie), and advisors (Dr. Amendt, Dr. Wehby and Dr. Butali) assembled in this proposal covers all areas of the much needed additional training necessary to accomplish the proposed research and training aims. They will provide guidance and facilitate the growth of the PI during the transition to independence. Although very well trained initially, the five years hiatus in the PI's career justify the need for additional training in the rapidly moving fields of epigenetics and big data applications. The proposed training and research aims are tailored to build upon the PI's previous experience and to provide the additional training in epigenetics and analytical methods necessary to propel the PI's development as an independent researcher able to integrate epigenetic and genetic data to study complex craniofacial birth defects.

抽象的 非综合征性口面裂（OFC）是人类最常见的颅面出生缺陷，影响 全球大约七百人中就有一人。全基因组连锁和关联研究已经确定 OFC 的几个风险等位基因；然而，它们仅占估计遗传力的一小部分。所以， 虽然正在进行的遗传和表达研究可能会在理解 OFC 的生物学基础，只有当易感性变异的相互作用时，才会出现更全面的情况 与其他因素（例如表观遗传变化）的关系也已确定。表观遗传修饰是一种可能的机制 环境因素和遗传变异可能会改变基因表达。 DNAm 是共价键 在核苷酸胞嘧啶上添加甲基 (CH3) 基团，这可能会导致转录发生变化 目标基因的活性。我们假设甲基化的变化以及由此产生的差异基因 表达是 OFC 的表观遗传风险因素，DNAm 介导 OFC 风险的遗传影响。我们的 主要目标是表征可能影响 OFC 风险的全基因组 DNAm 变异；并探索 OFC 病因学中涉及的遗传-表观遗传相互作用 (meQTL)。为此，该项目提出了 使用迄今为止最大的同卵双胞胎样本集和不一致的兄弟姐妹对的强大策略 非综合征 OFC 用于研究表观遗传风险因素。这是关键的一步，也是一种创新方法， 将能够揭示传统 GWAS 和 DNA 测序无法发现的表观遗传学风险因素 方法。本提案的中心假设将通过以下具体目标进行检验：（1） 确定同卵双胞胎中 OFC 不一致的全基因组 DNA 甲基化模式； (2) 探索 OFC 的病因学涉及遗传-表观遗传相互作用 (meQTL)。在目标 2 内，我们将尝试 复制初步分析中确定的遗传-表观遗传相互作用（自第一次分析以来获得） 提交此提案），以及目标 1 产生的热门点击，使用独立的裂痕不一致队列 兄弟姐妹对。杰出的导师团队（Jeff Murray 博士、Robert Philibert 博士、Mary Marazita 博士和 Moreno-Uribe 博士）、顾问（谢博士、Dr. Drake）、合作者（Lie 博士）和顾问（Amendt 博士、Dr. Drake） Wehby 和 Butali 博士）在本提案中汇集了急需的额外培训的所有领域 完成拟议的研究和培训目标所必需的。他们将提供指导并促进 PI 在向独立过渡期间的增长。尽管最初训练得很好，但五年的中断 在 PI 的职业生涯中，需要在快速发展的表观遗传学和大数据领域进行额外培训 应用程序。拟议的培训和研究目标是根据 PI 以前的经验量身定制的 并提供表观遗传学和分析方法方面的额外培训，以推动 PI 的发展 发展成为一名独立研究人员，能够整合表观遗传和遗传数据来研究复杂的 颅面部出生缺陷。