Genome-wide meta-analysis points to CTC1 and ZNf676 as genes regulating telomere homeostasis in humans

Massimo Mangino, Shih Jen Hwang, Timothy D. Spector, Steven Hunt, Masayuki Kimura, Annette L. Fitzpatrick, Lene Christiansen, Inge Petersen, Clara C. Elbers, Tamara Harris, Wei Chen, Sathanur R. Srinivasan, Jeremy D. Kark, Athanase Benetos, Said El shamieh, Sophie Visvikis-Siest, Kaare Christensen, Gerald S. Berenson, Ana M. Valdes, Ana Vinuela & 19 others Melissa Garcia, Donna K. Arnett, Ulrich Broeckel, Michael A. Province, James S. Pankow, Candace Kammerer, Yongmei Liu, Michael Nalls, Sarah Tishkoff, Fridtjof Thomas, Elad Ziv, Bruce M. Psaty, Joshua C. Bis, Jerome I. Rotter, Kent D. Taylor, Erin Smith, Nicholas J. Schork, Daniel Levy, Abraham Aviv

Research output: Contribution to journalArticle

109 Citations (Scopus)

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.

Original languageEnglish
Article numberdds382
Pages (from-to)5385-5394
Number of pages10
JournalHuman Molecular Genetics
Volume21
Issue number24
DOIs
Publication statusPublished - Dec 2012
Externally publishedYes

Fingerprint

Telomere Homeostasis
Telomere
Meta-Analysis
Genome
Leukocytes
Genes
Genome-Wide Association Study
Zinc Fingers
Point Mutation
Arabidopsis
Chromosomes
Alleles
Maintenance

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Mangino, M., Hwang, S. J., Spector, T. D., Hunt, S., Kimura, M., Fitzpatrick, A. L., ... Aviv, A. (2012). Genome-wide meta-analysis points to CTC1 and ZNf676 as genes regulating telomere homeostasis in humans. Human Molecular Genetics, 21(24), 5385-5394. [dds382]. https://doi.org/10.1093/hmg/dds382

Genome-wide meta-analysis points to CTC1 and ZNf676 as genes regulating telomere homeostasis in humans. / Mangino, Massimo; Hwang, Shih Jen; Spector, Timothy D.; Hunt, Steven; 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.; Vinuela, 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.

In: Human Molecular Genetics, Vol. 21, No. 24, dds382, 12.2012, p. 5385-5394.

Research output: Contribution to journalArticle

Mangino, M, Hwang, SJ, Spector, TD, Hunt, S, 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, Vinuela, 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 2012, 'Genome-wide meta-analysis points to CTC1 and ZNf676 as genes regulating telomere homeostasis in humans', Human Molecular Genetics, vol. 21, no. 24, dds382, pp. 5385-5394. https://doi.org/10.1093/hmg/dds382
Mangino, Massimo ; Hwang, Shih Jen ; Spector, Timothy D. ; Hunt, Steven ; 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. ; Vinuela, 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. / Genome-wide meta-analysis points to CTC1 and ZNf676 as genes regulating telomere homeostasis in humans. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 24. pp. 5385-5394.
@article{337b74d5572f46fcb0595d11edd45b6f,
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.",
author = "Massimo Mangino and Hwang, {Shih Jen} and Spector, {Timothy D.} and Steven Hunt and Masayuki Kimura and Fitzpatrick, {Annette L.} and Lene Christiansen and Inge Petersen and Elbers, {Clara C.} and Tamara Harris and Wei Chen and Srinivasan, {Sathanur R.} and Kark, {Jeremy D.} and Athanase Benetos and {El shamieh}, Said and Sophie Visvikis-Siest and Kaare Christensen and Berenson, {Gerald S.} and Valdes, {Ana M.} and Ana Vinuela and Melissa Garcia and Arnett, {Donna K.} and Ulrich Broeckel and Province, {Michael A.} and Pankow, {James S.} and Candace Kammerer and Yongmei Liu and Michael Nalls and Sarah Tishkoff and Fridtjof Thomas and Elad Ziv and Psaty, {Bruce M.} and Bis, {Joshua C.} and Rotter, {Jerome I.} and Taylor, {Kent D.} and Erin Smith and Schork, {Nicholas J.} and Daniel Levy and Abraham Aviv",
year = "2012",
month = "12",
doi = "10.1093/hmg/dds382",
language = "English",
volume = "21",
pages = "5385--5394",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "24",

}

TY - JOUR

T1 - Genome-wide meta-analysis points to CTC1 and ZNf676 as genes regulating telomere homeostasis in humans

AU - Mangino, Massimo

AU - Hwang, Shih Jen

AU - Spector, Timothy D.

AU - Hunt, Steven

AU - Kimura, Masayuki

AU - Fitzpatrick, Annette L.

AU - Christiansen, Lene

AU - Petersen, Inge

AU - Elbers, Clara C.

AU - Harris, Tamara

AU - Chen, Wei

AU - Srinivasan, Sathanur R.

AU - Kark, Jeremy D.

AU - Benetos, Athanase

AU - El shamieh, Said

AU - Visvikis-Siest, Sophie

AU - Christensen, Kaare

AU - Berenson, Gerald S.

AU - Valdes, Ana M.

AU - Vinuela, Ana

AU - Garcia, Melissa

AU - Arnett, Donna K.

AU - Broeckel, Ulrich

AU - Province, Michael A.

AU - Pankow, James S.

AU - Kammerer, Candace

AU - Liu, Yongmei

AU - Nalls, Michael

AU - Tishkoff, Sarah

AU - Thomas, Fridtjof

AU - Ziv, Elad

AU - Psaty, Bruce M.

AU - Bis, Joshua C.

AU - Rotter, Jerome I.

AU - Taylor, Kent D.

AU - Smith, Erin

AU - Schork, Nicholas J.

AU - Levy, Daniel

AU - Aviv, Abraham

PY - 2012/12

Y1 - 2012/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84870333736&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870333736&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds382

DO - 10.1093/hmg/dds382

M3 - Article

VL - 21

SP - 5385

EP - 5394

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 24

M1 - dds382

ER -