Identifying potentially modifiable exposures to improve telomere health and disease outcomes

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Project Summary/Abstract Telomeres are non-coding sequences at the end of chromosomes that shorten with each cell division as we age. Telomere length (TL) may be a global biomarker of health, as shorter telomere length is associated with poor survival, age-related diseases/conditions, and some cancers. Both genetic and non-genetic factors influence telomere length and the underlying mechanisms remain unclear. We propose to use UK Biobank data to delineate modifiable exposures that directly influence or moderate telomere length, and how the relationships influence health and risk of disease (responding to PA-19-073). UK Biobank offers an exceptionally large sample size (over 500,000 participants), with telomere length measures, genetic and phenotypic data. Most notably, it provides multidimensional data on exposures, covering early life, socio- economic factors, environmental exposures, psychologically traumatic events, plus lifestyle and behavioral factors, including accelerometer measures of physical activity. We hypothesize that identifying and characterizing behavioral and environmental factors associated with telomere length, especially in older groups, will inform future efforts to therapeutically target telomeres through personalized, non-pharmacological interventions. We also hypothesize that a better understanding of gene-environment interactions will support the use of telomere length measurement for monitoring individual health status, to alert health providers to the need for preventive and early health care, ultimately improving health outcomes. We aim to conduct an environment-wide association study (EWAS) to identify novel exposures and gene-environment interactions on telomere length. We also will examine the intermediate role of telomere length in the relationships between exposures and disease outcomes. Additionally, we aim to strengthen our EWAS by inherited genetic variants associated with exposures and telomere length, to investigate bidirectional exposure and TL causal relationships. As inherited genetic variants are unchanging during life, they can be used to conduct pseudo randomized trials to produce more robust associations to confounding and reverse causation. Our team is multidisciplinary, with expertise in statistical genetics, genetic epidemiology, bioinformatics, clinical geriatrics, and physical activity epidemiology. The team has already produced several leading outputs using UK Biobank data, including a study on telomere length and aging-related outcomes via genetic variants associated with telomere length. We request funding to extend this work to identify novel modifiable exposures influencing telomere length, and establish the path from modifiable exposures to telomere length and then health-related outcomes. Our findings will be useful to prioritize modifiable exposures for personalized interventions with the ultimate goal of improving telomere health and disease outcomes. In the future, we will seek to replicate our key findings, where possible, using the US Health and Retirement study samples and set up a CHARGE consortium collaboration (CHARGE: Cohorts for Heart and Aging Research in Genomic Epidemiology).