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Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.

TitleGenome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.
Publication TypeJournal Article
Year of Publication2012
AuthorsMangino, M, Hwang, S-J, Spector, TD, Hunt, SC, Kimura, M, Fitzpatrick, AL, Christiansen, L, Petersen, I, Elbers, CC, Harris, T, Chen, W, Srinivasan, SR, Kark, JD, Benetos, A, Shamieh, SEl, Visvikis-Siest, S, Christensen, K, Berenson, GS, Valdes, AM, Viñuela, A, Garcia, M, Arnett, DK, Broeckel, U, Province, MA, Pankow, JS, Kammerer, C, Liu, Y, Nalls, M, Tishkoff, S, Thomas, F, Ziv, E, Psaty, BM, Bis, JC, Rotter, JI, Taylor, KD, Smith, E, Schork, NJ, Levy, D, Aviv, A
JournalHum Mol Genet
Volume21
Issue24
Pagination5385-94
Date Published2012 Dec 15
ISSN1460-2083
KeywordsGenome-Wide Association Study, Humans, Kruppel-Like Transcription Factors, Telomere, Telomere Homeostasis, Telomere-Binding Proteins
Abstract<p>Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.</p>
DOI10.1093/hmg/dds382
Alternate JournalHum. Mol. Genet.
PubMed ID23001564
PubMed Central IDPMC3510758
Grant ListN01-HC-25195 / HC / NHLBI NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01AG62101 / AG / NIA NIH HHS / United States
AG-15928 / AG / NIA NIH HHS / United States
1R01AG032098-01A1 / AG / NIA NIH HHS / United States
AG-20098 / AG / NIA NIH HHS / United States
HL055673 / HL / NHLBI NIH HHS / United States
HL54515 / HL / NHLBI NIH HHS / United States
R01 AG016592 / AG / NIA NIH HHS / United States
HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
AG-027058 / AG / NIA NIH HHS / United States
R01AG21593 / AG / NIA NIH HHS / United States
/ / Intramural NIH HHS / United States
N01-HC-35129 / HC / NHLBI NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
HL54496 / HL / NHLBI NIH HHS / United States
1 R01 HL80698-01 / HL / NHLBI NIH HHS / United States
R01AG20132 / AG / NIA NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01 HC-15103 / HC / NHLBI NIH HHS / United States
HL54473 / HL / NHLBI NIH HHS / United States
HD-062783 / HD / NICHD NIH HHS / United States
AG-16592 / AG / NIA NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
N01-HC-45133 / HC / NHLBI NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
N01AG62103 / AG / NIA NIH HHS / United States
HHSN268201200036C / / PHS HHS / United States
HHSN268200782096C / / PHS HHS / United States
HL080295 / HL / NHLBI NIH HHS / United States
N01AG62106 / AG / NIA NIH HHS / United States
HL54495 / HL / NHLBI NIH HHS / United States
N01-HC-85239 / HC / NHLBI NIH HHS / United States
HD-061437 / HD / NICHD NIH HHS / United States
R01AG030678 / AG / NIA NIH HHS / United States
/ / Wellcome Trust / United Kingdom
AG 023629 / AG / NIA NIH HHS / United States
HL54471 / HL / NHLBI NIH HHS / United States
HL54509 / HL / NHLBI NIH HHS / United States
K24 CA169004 / CA / NCI NIH HHS / United States
HL54472 / HL / NHLBI NIH HHS / United States