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 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 journalArticle

34 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

    Fingerprint

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mangino, M., Christiansen, L., Stone, R., Hunt, S., 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