@article {6817, title = {DCAF4, a novel gene associated with leucocyte telomere length.}, journal = {J Med Genet}, volume = {52}, year = {2015}, month = {2015 Mar}, pages = {157-62}, 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{\texttimes}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{\texttimes}10(-3) and 2{\texttimes}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{\texttimes}10(-169) to 3.42{\texttimes}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.

}, keywords = {Alleles, Carrier Proteins, Gene Expression Regulation, Genome-Wide Association Study, Humans, Leukocytes, Melanoma, Risk Factors, Telomere, Telomere Homeostasis}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2014-102681}, author = {Mangino, Massimo and Christiansen, Lene and Stone, Rivka and Hunt, Steven C and Horvath, Kent and Eisenberg, Dan T A and Kimura, Masayuki and Petersen, Inge and Kark, Jeremy D and Herbig, Utz and Reiner, Alex P and Benetos, Athanase and Codd, Veryan and Nyholt, Dale R and Sinnreich, Ronit and Christensen, Kaare and Nassar, Hisham and Hwang, Shih-Jen and Levy, Daniel and Bataille, Veronique and Fitzpatrick, Annette L and Chen, Wei and Berenson, Gerald S and Samani, Nilesh J and Martin, Nicholas G and Tishkoff, Sarah and Schork, Nicholas J and Kyvik, Kirsten Ohm and Dalg{\r a}rd, Christine and Spector, Timothy D and Aviv, Abraham} }