DCAF4, a novel gene associated with leucocyte telomere length

Massimo Mangino, Lene Christiansen, Rivka Stone, Steven C 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 BatailleAnnette 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 journalJournal articleResearchpeer-review

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 over-represented 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
JournalJournal of Medical Genetics
Volume52
Issue number3
Pages (from-to)157-62
ISSN0022-2593
DOIs
Publication statusPublished - Mar 2015

Fingerprint

Telomere
Genome-Wide Association Study
Melanoma
Meta-Analysis
Population
Skin

Keywords

  • complex traits
  • telomere
  • cancer
  • skin
  • melanoma

Cite this

Mangino, M., Christiansen, L., Stone, R., Hunt, S. C., Horvath, K., Eisenberg, D. T. A., ... Aviv, A. (2015). DCAF4, a novel gene associated with leucocyte telomere length. Journal of Medical Genetics, 52(3), 157-62. https://doi.org/10.1136/jmedgenet-2014-102681
Mangino, Massimo ; Christiansen, Lene ; Stone, Rivka ; Hunt, Steven C ; 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. 157-62.
@article{4e41c6712f3445c2887315dc98ce8ed4,
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 over-represented 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.",
keywords = "complex traits, telomere, cancer, skin, melanoma",
author = "Massimo Mangino and Lene Christiansen and Rivka Stone and Hunt, {Steven C} 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 Shih-Jen Hwang 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",
note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",
year = "2015",
month = "3",
doi = "10.1136/jmedgenet-2014-102681",
language = "English",
volume = "52",
pages = "157--62",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "B M J Group",
number = "3",

}

Mangino, M, Christiansen, L, Stone, R, Hunt, SC, 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, S-J, 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. 157-62. 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 C; 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, 03.2015, p. 157-62.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - DCAF4, a novel gene associated with leucocyte telomere length

AU - Mangino, Massimo

AU - Christiansen, Lene

AU - Stone, Rivka

AU - Hunt, Steven C

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

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2015/3

Y1 - 2015/3

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 over-represented 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.

AB - 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 over-represented 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.

KW - complex traits

KW - telomere

KW - cancer

KW - skin

KW - melanoma

U2 - 10.1136/jmedgenet-2014-102681

DO - 10.1136/jmedgenet-2014-102681

M3 - Journal article

C2 - 25624462

VL - 52

SP - 157

EP - 162

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 3

ER -