DCAF4, a novel gene associated with leucocyte telomere length

Massimo Mangino, Lene Christiansen, Rivka Stone, Steven Hunt, Kent Horvath, Dan T A Eisenberg, Masayuki Kimura, Inge Petersen, Jeremy D. Kark, Utz Herbig, Alex P. Reiner, Athanase Benetos, Veryan Codd, Dale R. Nyholt, Ronit Sinnreich, Kaare Christensen, Hisham Nassar, Shih Jen Hwang, Daniel Levy, Veronique Bataille & 11 others Annette L. Fitzpatrick, Wei Chen, Gerald S. Berenson, Nilesh J. Samani, Nicholas G. Martin, Sarah Tishkoff, Nicholas J. Schork, Kirsten Ohm Kyvik, Christine Dalgård, Timothy D. Spector, Abraham Aviv

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR). Results: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10-10) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10-3 and 2×10-3, respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds ( p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly overrepresented for melanoma at p values ranging from 1.97×10-169 to 3.42×10-24. Conclusions: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

Original languageEnglish
Pages (from-to)157-162
Number of pages6
JournalJournal of Medical Genetics
Volume52
Issue number3
DOIs
Publication statusPublished - 2015
Externally publishedYes

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Telomere
Leukocytes
Genes
Genome-Wide Association Study
Melanoma
Meta-Analysis
Radiation
Population
Solar System
Skin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mangino, M., Christiansen, L., Stone, R., Hunt, S., Horvath, K., Eisenberg, D. T. A., ... Aviv, A. (2015). DCAF4, a novel gene associated with leucocyte telomere length. Journal of Medical Genetics, 52(3), 157-162. https://doi.org/10.1136/jmedgenet-2014-102681

DCAF4, a novel gene associated with leucocyte telomere length. / Mangino, Massimo; Christiansen, Lene; Stone, Rivka; Hunt, Steven; Horvath, Kent; Eisenberg, Dan T A; Kimura, Masayuki; Petersen, Inge; Kark, Jeremy D.; Herbig, Utz; Reiner, Alex P.; Benetos, Athanase; Codd, Veryan; Nyholt, Dale R.; Sinnreich, Ronit; Christensen, Kaare; Nassar, Hisham; Hwang, Shih Jen; Levy, Daniel; Bataille, Veronique; Fitzpatrick, Annette L.; Chen, Wei; Berenson, Gerald S.; Samani, Nilesh J.; Martin, Nicholas G.; Tishkoff, Sarah; Schork, Nicholas J.; Kyvik, Kirsten Ohm; Dalgård, Christine; Spector, Timothy D.; Aviv, Abraham.

In: Journal of Medical Genetics, Vol. 52, No. 3, 2015, p. 157-162.

Research output: Contribution to journalArticle

Mangino, M, Christiansen, L, Stone, R, Hunt, S, Horvath, K, Eisenberg, DTA, Kimura, M, Petersen, I, Kark, JD, Herbig, U, Reiner, AP, Benetos, A, Codd, V, Nyholt, DR, Sinnreich, R, Christensen, K, Nassar, H, Hwang, SJ, Levy, D, Bataille, V, Fitzpatrick, AL, Chen, W, Berenson, GS, Samani, NJ, Martin, NG, Tishkoff, S, Schork, NJ, Kyvik, KO, Dalgård, C, Spector, TD & Aviv, A 2015, 'DCAF4, a novel gene associated with leucocyte telomere length', Journal of Medical Genetics, vol. 52, no. 3, pp. 157-162. https://doi.org/10.1136/jmedgenet-2014-102681
Mangino, Massimo ; Christiansen, Lene ; Stone, Rivka ; Hunt, Steven ; Horvath, Kent ; Eisenberg, Dan T A ; Kimura, Masayuki ; Petersen, Inge ; Kark, Jeremy D. ; Herbig, Utz ; Reiner, Alex P. ; Benetos, Athanase ; Codd, Veryan ; Nyholt, Dale R. ; Sinnreich, Ronit ; Christensen, Kaare ; Nassar, Hisham ; Hwang, Shih Jen ; Levy, Daniel ; Bataille, Veronique ; Fitzpatrick, Annette L. ; Chen, Wei ; Berenson, Gerald S. ; Samani, Nilesh J. ; Martin, Nicholas G. ; Tishkoff, Sarah ; Schork, Nicholas J. ; Kyvik, Kirsten Ohm ; Dalgård, Christine ; Spector, Timothy D. ; Aviv, Abraham. / DCAF4, a novel gene associated with leucocyte telomere length. In: Journal of Medical Genetics. 2015 ; Vol. 52, No. 3. pp. 157-162.
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title = "DCAF4, a novel gene associated with leucocyte telomere length",
abstract = "Background: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR). Results: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10-10) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10-3 and 2×10-3, respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds ( p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly overrepresented for melanoma at p values ranging from 1.97×10-169 to 3.42×10-24. Conclusions: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.",
author = "Massimo Mangino and Lene Christiansen and Rivka Stone and Steven Hunt and Kent Horvath and Eisenberg, {Dan T A} and Masayuki Kimura and Inge Petersen and Kark, {Jeremy D.} and Utz Herbig and Reiner, {Alex P.} and Athanase Benetos and Veryan Codd and Nyholt, {Dale R.} and Ronit Sinnreich and Kaare Christensen and Hisham Nassar and Hwang, {Shih Jen} and Daniel Levy and Veronique Bataille and Fitzpatrick, {Annette L.} and Wei Chen and Berenson, {Gerald S.} and Samani, {Nilesh J.} and Martin, {Nicholas G.} and Sarah Tishkoff and Schork, {Nicholas J.} and Kyvik, {Kirsten Ohm} and Christine Dalg{\aa}rd and Spector, {Timothy D.} and Abraham Aviv",
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T1 - DCAF4, a novel gene associated with leucocyte telomere length

AU - Mangino, Massimo

AU - Christiansen, Lene

AU - Stone, Rivka

AU - Hunt, Steven

AU - Horvath, Kent

AU - Eisenberg, Dan T A

AU - Kimura, Masayuki

AU - Petersen, Inge

AU - Kark, Jeremy D.

AU - Herbig, Utz

AU - Reiner, Alex P.

AU - Benetos, Athanase

AU - Codd, Veryan

AU - Nyholt, Dale R.

AU - Sinnreich, Ronit

AU - Christensen, Kaare

AU - Nassar, Hisham

AU - Hwang, Shih Jen

AU - Levy, Daniel

AU - Bataille, Veronique

AU - Fitzpatrick, Annette L.

AU - Chen, Wei

AU - Berenson, Gerald S.

AU - Samani, Nilesh J.

AU - Martin, Nicholas G.

AU - Tishkoff, Sarah

AU - Schork, Nicholas J.

AU - Kyvik, Kirsten Ohm

AU - Dalgård, Christine

AU - Spector, Timothy D.

AU - Aviv, Abraham

PY - 2015

Y1 - 2015

N2 - Background: Leucocyte telomere length (LTL), which is fashioned by multiple genes, has been linked to a host of human diseases, including sporadic melanoma. A number of genes associated with LTL have already been identified through genome-wide association studies. The main aim of this study was to establish whether DCAF4 (DDB1 and CUL4-associated factor 4) is associated with LTL. In addition, using ingenuity pathway analysis (IPA), we examined whether LTL-associated genes in the general population might partially explain the inherently longer LTL in patients with sporadic melanoma, the risk for which is increased with ultraviolet radiation (UVR). Results: Genome-wide association (GWA) meta-analysis and de novo genotyping of 20 022 individuals revealed a novel association (p=6.4×10-10) between LTL and rs2535913, which lies within DCAF4. Notably, eQTL analysis showed that rs2535913 is associated with decline in DCAF4 expressions in both lymphoblastoid cells and sun-exposed skin (p=4.1×10-3 and 2×10-3, respectively). Moreover, IPA revealed that LTL-associated genes, derived from GWA meta-analysis (N=9190), are over-represented among genes engaged in melanoma pathways. Meeting increasingly stringent p value thresholds ( p<0.05, <0.01, <0.005, <0.001) in the LTL-GWA meta-analysis, these genes were jointly overrepresented for melanoma at p values ranging from 1.97×10-169 to 3.42×10-24. Conclusions: We uncovered a new locus associated with LTL in the general population. We also provided preliminary findings that suggest a link of LTL through genetic mechanisms with UVR and melanoma in the general population.

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