PheWAS and GWAS of Telomere Length to Understand Human Disease

摘要： 人类疾病受到遗传和环境因素之间复杂相互作用的影响。 确定能够超越这些复杂性的基因组生物标志物将非常重要。 端粒是覆盖染色体末端的重复DNA序列。它们是必要的， 维持染色体稳定性，并在细胞活力中发挥重要作用。随着人类年龄的增长， 随着每次细胞分裂而变短，从而为细胞提供内部生物钟， 生存能力。当端粒变得过短时，细胞进入复制性衰老。 端粒的失调在许多癌症中是常见的，并且端粒长度（TL）的可变性是已知的 与许多疾病有关。全基因组关联研究（GWAS）还发现 大约30个候选变异影响TL的正常变异，其中一些变异 与人类疾病有关。据推测，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。为了验证这个假设，我们 提出以下目标：（1）通过以下方法将数千种临床显著表型与TL相关联： 全表型关联研究（PheWAS），（2）进行TL的最大单个GWAS，以确定 与该性状相关的新变体，以及（3）鉴定与遗传相关的疾病。 通过PheWAS影响TL的变体。为了实现这些目标，这项研究将利用70，000 来自两个大型医疗系统的不同种族的DNA样本所有的DNA样本都与 基因组数据和长期电子健康记录。通过拟议的GWAS和PheWAS 通过这些实验，我们期望获得关于端粒生物学在人类中的重要性的知识。 健康及其对各种疾病的诊断效用。

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.