Unraveling correlations between Mendelian and common disease using functional genomics

使用功能基因组学揭示孟德尔与常见疾病之间的相关性

• 批准号: 9351765
• 负责人: Valerie A Arboleda
• 金额: $ 38.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351765
• 关键词: Acetylation; Acetyltransferase; Address; Affect; Autistic Disorder; Autoimmune Diseases; Behavioral; Biochemical; Biological; Biological Markers; Biological Process; Cell Line; ChIP-seq; Chromatin; Clinical; Code; Data; Dermal; Development; Developmental Delay Disorders; Diagnosis; Diagnostic; Disease; Epigenetic Process; Family; Family health status; Fibroblasts; Future; Gene Expression; Gene Expression Regulation; Gene Mutation; Gene Targeting; Generations; Genes; Genetic; Genomic approach; Genomics; Goals; Healthcare Systems; Hereditary Disease; High-Throughput Nucleotide Sequencing; Histones; Human Cell Line; Immunoprecipitation; Individual; Intelligence; Joints; Language; Left; Link; Lysine; Measures; Mendelian disorder; Modeling; Molecular; Motor; Mutation; Neurocognitive; Nuclear Protein; Pathway interactions; Patients; Phenotype; Population; Precision Medicine Initiative; Proteins; Rare Diseases; Research; Risk; Standardization; Surveys; Syndrome; Tail; Testing; Transcriptional Regulation; Untranslated RNA; Validation; Variant; base; cancer therapy; cell growth regulation; clinical biomarkers; combinatorial; data mining; disease phenotype; disorder risk; epigenetic marker; epigenome; epigenomics; executive function; exome sequencing; functional genomics; genetic disorder diagnosis; genetic variant; genome wide association study; genome-wide; genomic biomarker; genomic data; individual patient; individualized medicine; lens; novel; outcome forecast; precision medicine; psychosocial; trait; transcriptome; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Individualized diagnosis and treatment based on the integration of clinical, genomic, epigenetic and other biomarkers represent the promise of precision medicine. While most precision medicine initiatives are geared towards cancer treatment and common disease, which affect more than 5% of the population, this proposal seeks to bring the goals of precision medicine to those affected by rare Mendelian genetic diseases. The goal of my research group is to unravel the relationships between Mendelian and common disease through the lens of rare Mendelian syndromes. Our overarching approach will integrate multiple functional genomic studies (RNA-seq and ChIP-seq) from patients with rare Mendelian syndromes to publically available genome wide association study (GWAS) data. Using these data, we will achieve the parallel objectives of 1) revealing the underlying biological mechanisms of rare disease and 2) their intersection with genetic loci associated with common diseases. We will focus our study on the novel genetic syndrome of global developmental delay that we first identified as caused by de novo mutations in KAT6A (Lysine (K) acetyltransferase 6A). KAT6A belongs to a family of acetyltransferase genes and one of its main functions is to modify histones and control the expression of a wide set of downstream genes. In Aim 1, we will identify KAT6A target genes using patient- derived dermal fibroblast cell lines and generate functional genomic data such as RNA-seq and ChIP-seq. These data will be integrated to identify high priority target genes and functionally validated in human cell lines. Aim 2 will address the hypothesis that Mendelian disease mutations affect expression of genes underlying common disease (i.e. autoimmune disease, autism) thereby altering the risk of common disease. Neurocognitive, behavioral and developmental phenotyping will be performed to quantify co-existing common disease phenotypes and will be integrated with individual functional genomic data and disease-specific GWAS. Findings from these studies will advance our ability to interpret the influence of Mendelian gene mutations on common disease loci within a single individual, thus providing a critical link between Mendelian and common disease. In doing so, we will advance precision medicine approaches with respect to Mendelian disease, with the ultimate goal of identifying rational gene targets to use in identification of future therapies for these rare conditions.

项目摘要/摘要 基于临床，基因组，表观遗传和其他的整合的个性化诊断和治疗 生物标志物代表着精密医学的希望。虽然大多数精确的医学计划是装备的 该提议迈向影响超过5％人口的普通疾病，这会影响超过5％的人口 寻求将精确医学的目标带给受罕见的孟德尔遗传疾病影响的人。目标 我的研究小组是通过镜头揭示孟德尔和普通疾病之间的关系 罕见的孟德尔综合症。我们的总体方法将整合多种功能基因组研究 （RNA-SEQ和CHIP-SEQ）来自罕见Mendelian综合征患者到公开可用的基因组宽的患者 协会研究（GWAS）数据。使用这些数据，我们将实现1）揭示的并行目标 稀有疾病的潜在生物学机制和2）与遗传基因座相交的相交 常见疾病。我们将把研究重点放在全球发育延迟的新遗传综合症上 我们首先是由Kat6a（赖氨酸（K）乙酰转移酶6a）中的从头突变引起的。 Kat6a属于 乙酰基转移酶基因及其主要功能之一是修改组蛋白并控制 一组下游基因的表达。在AIM 1中，我们将使用患者确定Kat6a靶基因 衍生的皮肤成纤维细胞系并生成功能基因组数据，例如RNA-SEQ和CHIP-SEQ。 这些数据将集成以识别高优先级靶基因并在人体细胞系中进行功能验证。 AIM 2将解决Mendelian疾病突变影响基因表达的假设 常见疾病（即自身免疫性疾病，自闭症），从而改变了常见疾病的风险。 将进行神经认知，行为和发展表型，以量化共同存在的共同 疾病表型，并将与单个功能基因组数据和疾病特异性GWAS整合。 这些研究的发现将提高我们解释孟德尔基因突变对的能力 一个人内的普通疾病基因座，因此提供了门德利和普通之间的关键联系 疾病。在此过程中，我们将在孟德尔氏病方面提高精确医学方法 确定用于识别这些罕见的未来疗法的理性基因靶标的最终目标 状况。