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 Bataille; 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

doi:10.1136/jmedgenet-2014-102681

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 Bataille

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 journal › Article › Research › peer-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

Original language	English
Pages (from-to)	157-162
Number of pages	6
Journal	Journal of Medical Genetics
Volume	52
Issue number	3
DOIs	https://doi.org/10.1136/jmedgenet-2014-102681
Publication status	Published - 1 Mar 2015

Keywords

complex traits
telomere
cancer
skin
melanoma

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10.1136/jmedgenet-2014-102681

Cite this

Mangino, M., Christiansen, L., Stone, R., Hunt, S. C., Horvath, K., Eisenberg, D. T. A., Kimura, M., Petersen, I., Kark, J. D., Herbig, U., Reiner, A. P., Benetos, A., Codd, V., Nyholt, D. R., Sinnreich, R., Christensen, K., Nassar, H., Hwang, S.-J., Levy, D., ... 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

@article{4e2fb0cfa86e481e8ffe98e817e7a8d5,

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",

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 = mar,

day = "1",

doi = "10.1136/jmedgenet-2014-102681",

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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. 157-162. https://doi.org/10.1136/jmedgenet-2014-102681

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 - 2015/3/1

Y1 - 2015/3/1

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

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

KW - complex traits

KW - telomere

KW - cancer

KW - skin

KW - melanoma

U2 - 10.1136/jmedgenet-2014-102681

DO - 10.1136/jmedgenet-2014-102681

M3 - Article

SN - 0022-2593

VL - 52

SP - 157

EP - 162

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 3

ER -