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DCAF4, a novel gene associated with leucocyte telomere length.

aging

cancer

cardiovascular

genetics

senescence

telomere length

Authors: Massimo M. Mangino, Lene L. Christiansen, Rivka R. Stone, Steven C SC. Hunt, Kent K. Horvath, Dan T A DT. Eisenberg, Masayuki M. Kimura, Inge I. Petersen, Jeremy D JD. Kark, Utz U. Herbig, Alex P AP. Reiner, Athanase A. Benetos, Veryan V. Codd, Dale R DR. Nyholt, Ronit R. Sinnreich, Kaare K. Christensen, Hisham H. Nassar, Shih-Jen SJ. Hwang, Daniel D. Levy, Veronique V. Bataille, Annette L AL. Fitzpatrick, Wei W. Chen, Gerald S GS. Berenson, Nilesh J NJ. Samani, Nicholas G NG. Martin, Sarah S. Tishkoff, Nicholas J NJ. Schork, Kirsten Ohm KO. Kyvik, Christine C. Dalgård, Timothy D TD. Spector, Abraham A. Aviv
Published: 01/26/2015, Journal of medical genetics

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.

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.
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