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: 10675767
• 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/10675767
• 关键词: Aberrant DNA Methylation; Affect; Area; Behavioral; Big Data; Biological; Caring; Cleft Lip; Cleft Palate; Code; 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; 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; 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; 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 prediction; risk variant; transmethylation

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 非综合性口面裂（OFCS）是人类最常见的颅面出生缺陷，影响 全世界大约有700个人中有1个。全基因组联系和关联研究已经确定 OFC的几种风险等位基因；但是，他们解释了其估计遗传力的少数。所以， 尽管正在进行的遗传和表达研究可能会导致理解的重要进展 生物学基础的基础C，随着敏感性变体的相互作用，更全面的图片才会出现 建立了其他因素，例如表观遗传变化。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 将甲基（CH3）组添加到核苷酸胞嘧啶中，这可能导致转录变化 靶基因的活性。我们假设甲基化的变化和产生的差异基因 表达是OFC的表观遗传危险因素，DNAM介导OFCS风险中的遗传影响。我们的 主要目标是表征全基因组DNAM变异，这可能会影响OFC的风险；并探索 OFC病因涉及的遗传性雄性相互作用（MEQTL）。为此，该项目提出了一个 使用单卵双胞胎和兄弟姐妹对的最大样品集（迄今为止）不一致的强大策略 非综合症OFC用于研究表观遗传危险因素。这是一个关键步骤和创新的方法 将允许发现常规GWA和DNA测序不可见的表观遗传学风险因素 方法。该提案的中心假设将通过以下特定目的进行测试：（1）至 确定全基因组DNA甲基化模式在MZ双胞胎中与OFC不一致； （2）探索 OFC的病因涉及的遗传性景观相互作用（MEQTL）。在目标2中，我们将尝试 复制初步分析中鉴定的遗传性诊断相互作用（从第一次获得 提交此提案），并使用独立的Cleft Cledant群体，由AIM 1产生的最高命中 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（Xie博士和Drake博士），合作者（Lie博士）和顾问（Amendt博士，博士 Wehby和Butali博士在此提案中汇集了尤其需要额外培训的所有领域 完成拟议的研究和培训目的所必需的。他们将提供指导并促进 PI在过渡到独立性期间的增长。虽然最初训练经过良好的训练，但五年中断 在Pi的职业中 申请。拟议的培训和研究目标是为了建立PI以前的经验而量身定制的 并提供有关推动PI所需的表观遗传学和分析方法的额外培训 作为一名独立研究人员的发展，能够整合表观遗传和遗传数据以研究复杂 颅面出生缺陷。