Genetic and Clinical Determinants of Telomere Length

Numerous studies have established connections between leukocyte telomere length (LTL) and genetics and health. However, these studies have concentrated on specific diseases or GWAS analyses. We sought to explore the interplay between LTL, genomics, and human health by examining two vast patient populations obtained from the Vanderbilt University and Marshfield Clinic bio banks. These patient populations were linked to genomic and phenomic data from medical records. Our GWAS validated 11 genetic loci already associated with LTL, along with two novel loci in SCNN1D and PITPNM1. Using PheWAS, we identified 67 different clinical phenotypes connected with either short or long LTL. Our research showed that various diseases linked with LTL were related to each other but were largely independent of LTL genetics. Additionally, we found that age of death was related to LTL regardless of length. Individuals with very short LTL (< -1.5 standard deviation) died 10.4 years earlier than those with average LTL (mean age of death = 74.2 years). Similarly, those with very long LTL (> 1.5 SD) died 1.9 years earlier than those with average LTL. This aligns with our PheWAS results that show diseases associated with both short and long LTL. Finally, we discovered that the genome (12.8%), age (8.5%), the phenome (1.5%) and sex (0.9%) all together explained 23.7% of LTL variance. These findings underscore the need for additional research to understand the multifaceted connections between TL biology and human health over time.]]>
The study population was derived from the Vanderbilt University BioVU cohort and the Marshfield Clinic Health System Personalized Medicine Research Study (PMRP) cohort. Only white European subjects were included in our study. Individuals under 20 years of age at time of blood draw, for which DNA was extracted for genotyping and telomere length measurement, were excluded. Additionally, individuals with a history of hematologic malignancies were excluded. This was to reduce the probability of somatic events having a non normal effect on LTL. These included individuals with: Cancer of other lymphoid, histiocytic tissue Non-Hodgkins lymphoma Nodular lymphoma Reticulosarcoma Lymphosarcoma Large cell lymphoma Leukemia Lymphoid leukemia Lymphoid leukemia, acute Lymphoid leukemia, chronic Myeloid leukemia Myeloid leukemia, acute Myeloid leukemia, chronic Monocytic leukemia Multiple myeloma ]]>