Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs

Abstract

Telomeres play a central role in cellular senescence and cancer pathobiology and are associated with age-related diseases such as atherosclerosis and dementia. Telomere length varies between individuals of the same age, is influenced by DNA-damaging factors such as oxidative stress, and is heritable. We performed a quantitative-trait linkage analysis using an approximate 10-cM genomewide map for mean leukocyte terminal-restriction fragment (TRF) lengths measured by Southern blotting, in 2,050 unselected women aged 18-80 years, comprising 1,025 complete dizygotic twin pairs. Heritability of mean batch-adjusted TRF was 36% (95% confidence interval [CI] 18%-48%), with a large common environmental effect of 49% (95% CI 40%-58%). Significant linkage was observed on chromosome 14 (LOD 3.9) at 14q23.2, and suggestive linkage at 10q26.13 (LOD 2.4) and 3p26.1 (LOD 2.7). This is the first report of loci, mapped in a sample of healthy individuals, that influence mean telomere variation in humans.

Figure 1

Chromosomal LOD-score results for batch-adjusted TRF length, including a random effect for common environment and covariates BMI and donor age.

Figure 2

LOD-score results for batch-adjusted TRF length, analyzed with and without covariates BMI and donor age. Both genome scans included a random effect for common environment. For graph labeling purposes, marker positions are evenly spaced and are accurate only for order. Potential candidate genes for each linkage peak include chromosome 3 (RAD18 = postreplication repair protein; FANCD2 = Fanconi anemia complementation group D2 protein; XPC = xeroderma pigmentosum, complementation group C) (A), chromosome 10 (TNKS2 = tankyrase, TRF1-interacting ankyrin-related; HELLS = helicase, lymphoid-specific; PDCD4 = programmed cell death 4) (B), and chromosome 14 (MNAT1 = ménage à trois 1; RAD51L1 = RAD51-like 1; SIPA1L1 = signal-induced proliferation-associated 1 like 1) (C).