DCAF4, a novel gene associated with leucocyte telomere length

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, V., 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., Dalgard, C., Spector, T.D., & Aviv, A. (2015) DCAF4, a novel gene associated with leucocyte telomere length. Journal of Medical Genetics, 52(3), pp. 157-162.

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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.

Impact and interest:

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ID Code: 91780
Item Type: Journal Article
Refereed: Yes
DOI: 10.1136/jmedgenet-2014-102681
ISSN: 1468-6244
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 12 Jan 2016 04:28
Last Modified: 13 Jan 2016 01:42

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