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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要基于临床、基因组、表观遗传学等融合的个体化诊疗生物标志物代表了精准医学的前景。虽然大多数精准医疗计划都是针对针对影响超过 5% 人口的癌症治疗和常见疾病，该提案致力于将精准医学的目标带给那些患有罕见孟德尔遗传病的人。目标我的研究小组的目标是通过镜头揭示孟德尔与常见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）从罕见孟德尔综合征患者到公开可用的全基因组关联研究（GWAS）数据。使用这些数据，我们将实现以下并行目标：1) 揭示罕见疾病的潜在生物学机制，2）它们与相关遗传位点的交叉常见疾病。我们将把研究重点放在全球发育迟缓的新型遗传综合症上我们首先确定是由 KAT6A（赖氨酸 (K) 乙酰转移酶 6A）的从头突变引起的。 KAT6A所属属于乙酰转移酶基因家族，其主要功能之一是修饰组蛋白并控制一系列广泛的下游基因的表达。在目标 1 中，我们将使用患者识别 KAT6A 靶基因衍生的真皮成纤维细胞系并生成功能基因组数据，例如 RNA-seq 和 ChIP-seq。这些数据将被整合以识别高优先级目标基因，并在人类细胞系中进行功能验证。目标 2 将解决孟德尔疾病突变影响潜在基因表达的假设常见疾病（即自身免疫性疾病、自闭症），从而改变常见疾病的风险。将进行神经认知、行为和发育表型分析，以量化共存的常见现象疾病表型，并将与个体功能基因组数据和疾病特异性 GWAS 整合。这些研究的结果将提高我们解释孟德尔基因突变对健康的影响的能力。单个个体内的常见疾病位点，从而在孟德尔和常见疾病之间提供了关键联系疾病。在此过程中，我们将推进孟德尔疾病的精准医学方法，最终目标是确定合理的基因靶点，用于识别这些罕见疾病的未来疗法状况。