Exome Sequencing Analysis Identifies Rare Variants in ATM and RPL8 That Are Associated With Shorter Telomere Length

Ashley van der Spek, Sophie C. Warner, Linda Broer, Christopher P. Nelson, Dina Vojinovic, Shahzad Ahmad, Pascal P. Arp, Rutger W.W. Brouwer, Matthew Denniff, Mirjam C.G.N. van den Hout, Jeroen G.J. van Rooij, Robert Kraaij, Wilfred F.J. van IJcken, Nilesh J. Samani, M. Arfan Ikram, André G. Uitterlinden, Veryan Codd, Najaf Amin, Cornelia M. van Duijn

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6 Citations (Scopus)


Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family (ERF) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based ERF study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length (p-value < 1.42 × 10–7, minor allele frequency of 0.2–0.5%) in the ERF study. Eight of these variants (in C11orf65, ACAT1, NPAT, ATM, KDELC2, and EXPH5) were located on chromosome 11q22.3 that contains ATM, a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS (p-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in RPL8 (p-value = 1.48 × 10−6), which has previously been associated with age. Additionally, a novel rare variant in the known RTEL1 locus showed suggestive evidence for association (p-value = 1.18 × 10–4) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.

Original languageEnglish
Article number337
JournalFrontiers in Genetics
Publication statusPublished - 30 Apr 2020
Externally publishedYes


  • aging
  • ATM
  • meta-analysis
  • RPL8
  • telomere
  • whole exome sequencing


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