title: Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.
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.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kimura
authors.forename: Annette L
authors.initials: AL
authors.lastname: Fitzpatrick
authors.forename: Lene
authors.initials: L
authors.lastname: Christiansen
authors.forename: Inge
authors.initials: I
authors.lastname: Petersen
authors.forename: Clara C
authors.initials: CC
authors.lastname: Elbers
authors.forename: Tamara
authors.initials: T
authors.lastname: Harris
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Sathanur R
authors.initials: SR
authors.lastname: Srinivasan
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Kark
authors.forename: Athanase
authors.initials: A
authors.lastname: Benetos
authors.forename: Said
authors.initials: S
authors.lastname: El Shamieh
authors.forename: Sophie
authors.initials: S
authors.lastname: Visvikis-Siest
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Berenson
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.forename: Ana
authors.initials: A
authors.lastname: Viñuela
authors.forename: Melissa
authors.initials: M
authors.lastname: Garcia
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.forename: Candace
authors.initials: C
authors.lastname: Kammerer
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Michael
authors.initials: M
authors.lastname: Nalls
authors.forename: Sarah
authors.initials: S
authors.lastname: Tishkoff
authors.forename: Fridtjof
authors.initials: F
authors.lastname: Thomas
authors.forename: Elad
authors.initials: E
authors.lastname: Ziv
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Erin
authors.initials: E
authors.lastname: Smith
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Abraham
authors.initials: A
authors.lastname: Aviv
mesh_terms: D055106:Genome-Wide Association Study; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D016615:Telomere / Q000378:metabolism; D059505:Telomere Homeostasis / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000235:genetics*
chemical_list: C544945:Ctc1 protein, human; D051741:Kruppel-Like Transcription Factors; D034501:Telomere-Binding Proteins; C523963:ZNF674 protein, human