Article

Genome-Wide Association Study of Relative Telomere Length

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS ONE (Impact Factor: 3.53). 05/2011; 6(5):e19635. DOI: 10.1371/journal.pone.0019635
Source: PubMed

ABSTRACT Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses' Health Study and Women's Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = -0.03, P = 0.003) identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.

Download full-text

Full-text

Available from: Sharon A Savage, Jul 28, 2015
0 Followers
 · 
146 Views
  • Source
    • "The majority of our candidate genes were selected based on three prior studies of telomere-related genes (Mirabello et al., 2012, 2010; Nan et al., 2011b) and one study of arsenic exposure, telomere length, and gene expression (Li et al., 2012). We also included all 11 genes reported in recent genome-wide association studies of telomere length (Codd et al., 2010; Gu et al., 2011; Levy et al., 2010; Mangino et al., 2012, 2009; Prescott et al., 2011): ZNF676, CTC1, OBFC1, TERC, DHX35, WDR65, PELI2, KPNA5, SLC44A4, CXCR4 and CELF4 (BRUNOL4). In addition, we included 2 genes related to telomere biology (OGG1 and ERCC1) (Lu and Liu, 2010; Vannier et al., 2009) whose expression was reported to be associated with arsenic exposure among individuals in Inner Mongolia, China (Mo et al., 2009a, 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water. We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1799 individuals. Association between arsenic exposure and a qPCR-based telomere length measure was assessed among 167 individuals. Urinary arsenic was possitively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P<0.00035, Bonferroni-corrected threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction =0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02). Our findings suggest that arsenic's carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes. Copyright © 2014 Elsevier Inc. All rights reserved.
    Environmental Research 11/2014; 136C:462-469. DOI:10.1016/j.envres.2014.09.040 · 3.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In humans, autosomal dominant or X-linked disease can arise through a phenomenon termed haploinsufficiency, where one remaining wild-type allele is insufficient for function. In model organisms, the impact of heterozygosity can be tested directly with engineered mutant alleles or in a hemizygous state where the expression of one allele is abrogated completely. This review will focus on haploinsufficiency as it relates to telomerase and telomere length maintenance and, citing selected examples in various model organisms, it will discuss how the problem of gene dosage relates to telomere function in normal and diseased states.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 11/2011; 730(1-2):37-42. DOI:10.1016/j.mrfmmm.2011.11.004 · 4.44 Impact Factor
  • Source
    12/2011; 2(6):444-8.
Show more