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PMID: 23001564 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

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

Human molecular genetics ·Vol. 21 ·No. 24 ·2012-12-15 ·Pages 5385-94

Mangino M, Hwang SJ, Spector TD, Hunt SC, Kimura M, Fitzpatrick AL, Christiansen L, Petersen I, Elbers CC, Harris T, Chen W, Srinivasan SR, Kark JD, Benetos A, El Shamieh S, 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

Abstract

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.

MeSH Terms
Genome-Wide Association Study Humans Kruppel-Like Transcription Factors Telomere/metabolism Telomere Homeostasis/genetics Telomere-Binding Proteins/genetics
Chemicals
Ctc1 protein, human Kruppel-Like Transcription Factors Telomere-Binding Proteins ZNF674 protein, human
Authors & Affiliations
39 authors, click to expand affiliations / ORCID
Mangino Massimo
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Hwang Shih-Jen
Spector Timothy D
Hunt Steven C
Kimura Masayuki
Fitzpatrick Annette L
Christiansen Lene
Petersen Inge
Elbers Clara C
Harris Tamara
Chen Wei
Srinivasan Sathanur R
Kark Jeremy D
Benetos Athanase
El Shamieh Said
Visvikis-Siest Sophie
Christensen Kaare
Berenson Gerald S
Valdes Ana M
Viñuela Ana
Garcia Melissa
Arnett Donna K
Broeckel Ulrich
Province Michael A
Pankow James S
Kammerer Candace
Liu Yongmei
Nalls Michael
Tishkoff Sarah
Thomas Fridtjof
Ziv Elad
Psaty Bruce M
Bis Joshua C
Rotter Jerome I
Taylor Kent D
Smith Erin
Schork Nicholas J
Levy Daniel
Aviv Abraham
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Article Info
Journal
Human molecular genetics
Abbr.
Hum Mol Genet
ISSN
1460-2083
DOI
10.1093/hmg/dds382
Published
2012-12-15
Epub
2012-00-21
Pages
5385-94
Language
English
Region
England
NLM ID
9208958
PMCID
PMC3510758
Subset
IM
Grants
NHLBI NIH HHS · N01-HC-25195 · United States
NCATS NIH HHS · UL1TR000124 · United States
Wellcome Trust · United Kingdom
NHLBI NIH HHS · HHSN268201200036C · United States
NIA NIH HHS · AG-15928 · United States
NIA NIH HHS · 1R01AG032098-01A1 · United States
NHLBI NIH HHS · N01-HC-85086 · United States
NIA NIH HHS · AG-027058 · United States
NIA NIH HHS · R01AG21593 · United States
NIA NIH HHS · R01AG20132 · United States
NICHD NIH HHS · HD-062783 · United States
NHLBI NIH HHS · N01-HC-85239 · United States
NHLBI NIH HHS · HL54472 · United States
NHLBI NIH HHS · HL105756 · United States
NIA NIH HHS · N01AG62101 · United States
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NIA NIH HHS · R01 AG016592 · United States
NHLBI NIH HHS · HL087652 · United States
NCATS NIH HHS · UL1 TR000124 · United States
NIA NIH HHS · AG-20098 · United States
NHLBI NIH HHS · HL055673 · United States
NHLBI NIH HHS · N01-HC-35129 · United States
NHLBI NIH HHS · N01 HC-55222 · United States
NHLBI NIH HHS · HL54496 · United States
NHLBI NIH HHS · 1 R01 HL80698-01 · United States
NHLBI NIH HHS · N01-HC-75150 · United States
NHLBI NIH HHS · N01 HC-15103 · United States
NHGRI NIH HHS · HHSN268200782096C · United States
Intramural NIH HHS · United States
NHLBI NIH HHS · HL54473 · United States
NIA NIH HHS · AG-16592 · United States
NIDDK NIH HHS · DK063491 · United States
NHLBI NIH HHS · N01-HC-45133 · United States
NHLBI NIH HHS · N01-HC-85079 · United States
NIA NIH HHS · N01AG62103 · United States
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NHLBI NIH HHS · HL54509 · United States
NCI NIH HHS · K24 CA169004 · United States
External Links
PubMed source DOI: 10.1093/hmg/dds382 PMC Full Text View journal details
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