Genetic Interactions between TERT and Mitochondrial DNA Variants Modulate Leukocyte Telomere Length in UK Biobank

Poster Abstract: Farnoosh Ghaffaran, PhD Student, University of Leicester

Abstract

Background: Telomeres are repetitive DNA sequences that cap chromosome ends and help maintain genomic stability. Telomere length (TL) is widely recognised as a biomarker of cellular ageing, with shorter TL associated with ageing and multiple age-related diseases. Mitochondria, the organelles responsible for cellular energy production, also contribute to ageing. Mitochondrial dysfunction increases reactive oxygen species, which accelerates telomere shortening, while telomere damage can impair mitochondrial biogenesis. Together, these observations suggest bidirectional crosstalk between mitochondrial function and TL. We investigated whether this crosstalk is mediated by interactions between mitochondrial DNA (mtDNA) variants and nuclear DNA variants at TERT, a key telomere-regulating gene. Using UK Biobank data, we fitted linear regression models for leukocyte telomere length (LTL) that included age, sex, ancestry principal components, the main effects of each TERT and mtDNA variant, and an interaction term for each TERT–mtDNA variant pair. After correcting for multiple testing, we identified four TERT–mtDNA variant pairs with interaction terms significantly associated with LTL. 

Conclusions: These findings support the presence of mitochondrial–nuclear crosstalk in human telomere regulation and may help refine our understanding of LTL biology, with potential implications for improving risk prediction and treatment of age-related diseases.