PheWAS and GWAS of Telomere Length to Understand Human Disease

利用端粒长度的 PheWAS 和 GWAS 了解人类疾病

基本信息

批准号：
10664860
负责人：
Scott Joseph Hebbring
金额：
$ 44.38万
依托单位：
MARSHFIELD CLINIC RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-16 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10664860
关键词：
African American population Age Benign Biological Biological Assay Biological Clocks Biology Breast Cell Aging Cell Survival Cells Chromosomal Stability Chromosomes Clinic Code Complex DNA DNA Sequence Data Diagnostic Disease Electronic Health Record Environmental Risk Factor Etiology Future Genes Genetic Genetic Predisposition to Disease Genome Genomics Genotype Glioma Goals Health Healthcare Systems Human Individual International Classification of Disease Codes Knowledge Length Link Malignant Neoplasms Measures Medical Mendelian randomization Methodological Studies Pancreas Participant Patients Phenotype Play Population Population Heterogeneity Process Property Prostate RNA Risk Role Sampling Telomerase Testing Time Transcend Universities Variant bead chip biobank clinically significant diagnostic value ethnic diversity exome experimental study follow-up functional genomics genetic variant genome integrity genome wide association study genome-wide genomic biomarker genomic data human disease illness length innovation insight lifetime risk novel personalized medicine phenome phenotypic data racial diversity telomere trait tumor tumorigenesis whole genome

项目摘要

ABSTRACT: Human diseases are influenced by complex interactions between genetic and environmental factors. Identifying genomic biomarkers that can transcend these complexities would be of great importance. Telomeres are repetitive DNA sequences that cap the ends of chromosomes. They are necessary for maintaining chromosomal stability and play an important role in cell viability. As humans age, telomeres become shorter with every cellular division thus providing the cell with an internal biological clock for viability. When telomeres become excessively short, the cell enters replicative senescence. Dysregulation of telomeres is common in many cancers, and variability in telomere length (TL) is known to be associated with many diseases. Genome-wide association studies (GWASs) have also identified approximately 30 candidate variants that influence normal variation in TL, and some of these variants have been linked to human disease. It is hypothesized that TL, and variants that are associated with TL, may provide diagnostic and predictive information for many diseases. To test this hypothesis, we propose the following aims: (1) associate thousands of clinically significant phenotypes with TL by phenome-wide association studies (PheWAS), (2) conduct the largest single GWAS of TL to identify novel variants associated with the trait, and (3) identify diseases that are associated with genetic variants that influence TL by PheWAS. To accomplish these aims, this study will leverage 70,000 ethnically diverse DNA samples from two large healthcare systems. All DNA samples are linked to genomic data and long-term electronic health records. Through the proposed GWAS and PheWAS experiments, we expect to gain knowledge concerning the importance of telomere biology in human health and its diagnostic utility for various diseases.

抽象的：人类疾病受遗传和环境因素之间复杂相互作用的影响。确定可以超越这些复杂性的基因组生物标志物将非常重要。端粒是重复的DNA序列，限制染色体的末端。它们是必要的保持染色体稳定性并在细胞活力中起重要作用。随着人类的年龄，端粒每种细胞分裂都变得短，从而为细胞提供了一个内部生物时钟生存能力。当端粒过剩时，细胞会进入复制衰老。端粒的失调在许多癌症中很常见，端粒长度（TL）的变化是已知的与许多疾病有关。全基因组关联研究（GWASS）也已经鉴定影响TL正常变异的大约30种候选变异，其中一些变异变异与人类疾病有关。假设TL和与之相关的变体 TL可以为许多疾病提供诊断和预测信息。为了检验这一假设，我们提出以下目的：（1）将数千种临床上重要的表型与TL相关联全球范围的关联研究（PHEWAS），（2）进行TL的最大单个GWA 与性状相关的新型变种，（3）识别与遗传有关的疾病影响Phewas的TL的变体。为了实现这些目标，本研究将利用70,000 来自两个大型医疗系统的种族多样性的DNA样本。所有DNA样品都链接到基因组数据和长期电子健康记录。通过拟议的GWAS和Phewas 实验，我们希望获得有关端粒生物学重要性的知识健康及其针对各种疾病的诊断实用程序。