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.