Genetically Increased Telomere Length and Aging-Related Traits in the U.K. Biobank

Abstract

Telomere length (TL) shortens over time in most human cell types and is a potential biomarker of aging. However, the causal association of TL on physical and cognitive traits that decline with age has not been extensively examined in middle-aged adults. Using a Mendelian randomization (MR) approach, we utilized genetically increased TL (GI-TL) to estimate the impact of TL on aging-related traits among U.K. Biobank (UKB) participants (age 40-69 years). We manually curated 53 aging-related traits from the UKB and restricted to unrelated participants of British ancestry (n = 337,522). We estimated GI-TL as a linear combination of nine TL-associated single nucleotide polymorphisms (SNPs), each weighted by its previously-reported association with leukocyte TL. Regression models were used to assess the associations between GI-TL and each trait. We obtained MR estimates using the two-sample inverse variance weighted (IVW) approach. We identified six age-related traits associated with GI-TL (Bonferroni-corrected threshold p < .001): pulse pressure (PP) (p = 5.2 × 10-14), systolic blood pressure (SBP) (p = 2.9 × 10-15), diastolic blood pressure (DBP) (p = 5.5 × 10-6), hypertension (p = 5.5 × 10-11), forced expiratory volume (FEV1) (p = .0001), and forced vital capacity (FVC) (p = 3.8 × 10-6). Under MR assumptions, one standard deviation increase in TL (~1,200 base pairs) increased PP, SBP, and DBP by 1.5, 2.3, and 0.8 mmHg, respectively, while FEV1 and FVC increased by 34.7 and 52.2 mL, respectively. The observed associations appear unlikely to be due to selection bias based on analyses including inverse probability weights and analyses of simulated data. These findings suggest that longer TL increases pulmonary function and blood pressure traits among middle-aged UKB participants.

Keywords: Telomeres; Blood pressure; Mendelian randomization; Polygenic scores; Pulmonary function.