Epigenome-wide association study of leukocyte telomere length

Abstract

Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) – the Framingham Heart Study, the Jackson Heart Study, the Women’s Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P<1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.

Associations between DNA methylation and telomere length during early life: insight from wild zebra finches (Taeniopygia guttata)

“…Indeed, while telomeres themselves do not contain CpG sites, decreases in global and subtelomeric DNAm are known to be concomitant with increased homologous recombination between telomeric sequences and dramatically elongated telomeres in mouse cells (Gonzalo et al, 2006). Additionally, a negative relationship between telomere length and genome-wide (Lee et al, 2019) and gene-specific (Lee et al, 2019;Buxton et al, 2014) DNAm has been described in humans (however, this relationship may be complicated as a positive relationship has been detected in a different correlative study (Dong et al, 2018)). Evidence also suggests that short telomeres have specific epigenetic marks that may facilitate their preferential elongation (Hemann, Strong, Hao, & Greider, 2001;de Lange, 2005).…”

ARID3a expression in human hematopoietic stem cells is associated with distinct gene patterns in aged individuals

“…We considered that this variability might reflect variations in biological age versus chronological age. Telomere length has been used as a biologic measure of cellular age [ 33 , 34 ], and telomeres in hematopoietic cells from aged persons have been reported to be shortened compared to those from younger individuals [ 8 ]. Therefore, we chose individual HSC samples of both young and aged donor HSCs in Fig.…”

The Effect of Alcohol on Telomere Length: A Systematic Review of Epidemiological Evidence and a Pilot Study during Pregnancy

“…Although TL is highly inherited—with heritability estimates ranging from ~30% to ~80% [ 4 ]—only a small proportion of the genetic variants in telomere maintenance genes explains this variance [ 4 ]. More recently, an epigenome-wide association study of leukocyte TL has also demonstrated that DNA methylation of more than 800 CpG sites is associated with TL, and that these loci are within genes involved in circadian rhythm, coagulation, and wound healing [ 5 ]. These findings partially explain why TL considerably varies between individuals, even among those of the same chronological age, and suggest the involvement of other factors, including environmental exposures, behaviors, and diseases [ 5 ].…”

“…More recently, an epigenome-wide association study of leukocyte TL has also demonstrated that DNA methylation of more than 800 CpG sites is associated with TL, and that these loci are within genes involved in circadian rhythm, coagulation, and wound healing [ 5 ]. These findings partially explain why TL considerably varies between individuals, even among those of the same chronological age, and suggest the involvement of other factors, including environmental exposures, behaviors, and diseases [ 5 ]. Its presumed role in biological aging, in fact, means that TL has emerged as a potential biomarker of age-related diseases, such as cancer and cardiometabolic diseases [ 6 ].…”