%0 Journal Article %J J Med Genet %D 2015 %T DCAF4, a novel gene associated with leucocyte telomere length. %A Mangino, Massimo %A Christiansen, Lene %A Stone, Rivka %A Hunt, Steven C %A Horvath, Kent %A Eisenberg, Dan T A %A Kimura, Masayuki %A Petersen, Inge %A Kark, Jeremy D %A Herbig, Utz %A Reiner, Alex P %A Benetos, Athanase %A Codd, Veryan %A Nyholt, Dale R %A Sinnreich, Ronit %A Christensen, Kaare %A Nassar, Hisham %A Hwang, Shih-Jen %A Levy, Daniel %A Bataille, Veronique %A Fitzpatrick, Annette L %A Chen, Wei %A Berenson, Gerald S %A Samani, Nilesh J %A Martin, Nicholas G %A Tishkoff, Sarah %A Schork, Nicholas J %A Kyvik, Kirsten Ohm %A Dalgård, Christine %A Spector, Timothy D %A Aviv, Abraham %K Alleles %K Carrier Proteins %K Gene Expression Regulation %K Genome-Wide Association Study %K Humans %K Leukocytes %K Melanoma %K Risk Factors %K Telomere %K Telomere Homeostasis %X

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.

%B J Med Genet %V 52 %P 157-62 %8 2015 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/25624462?dopt=Abstract %R 10.1136/jmedgenet-2014-102681