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Title: DCAF4, a novel gene associated with leucocyte telomere length.
Authors: Mangino, M.
Christiansen, L.
Stone, R.
Hunt, S. C.
Horvath, K.
Eisenberg, D. T.
Kimura, M.
Petersen, I.
Kark, J. D.
Herbig, U.
Reiner, A. P.
Benetos, A.
Codd, Veryan
Nyholt, D. R.
Sinnreich, R.
Christensen, K.
Nassar, H.
Hwang, S. J.
Levy, D.
Bataille, V.
Fitzpatrick, A. L.
Chen, W
Berenson, G. S.
Samani, N. J.
Martin, N. G.
Tishkoff, S.
Schork, N. J.
Kyvik, K. O.
Dalgård, C.
Spector, T. D.
Aviv, A.
First Published: 26-Jan-2015
Publisher: BMJ Publishing Group
Citation: Journal of Medical Genetics, 2015, 52 (3), pp. 157-162
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.
DOI Link: 10.1136/jmedgenet-2014-102681
ISSN: 0022-2593
eISSN: 1468-6244
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2015. Licensee: BMJ. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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