title: DCAF4, a novel gene associated with leucocyte telomere length.
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.
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas' Foundation Trust, London, UK.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.affiliation: Epidemiology Unit, The Danish Aging Research Center and The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark Department of Clinical Genetics, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: Lene
authors.initials: L
authors.lastname: Christiansen
authors.affiliation: Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Rivka
authors.initials: R
authors.lastname: Stone
authors.affiliation: Cardiovascular Genetics Division, Department of Medicine, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Hunt
authors.affiliation: Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Kent
authors.initials: K
authors.lastname: Horvath
authors.affiliation: Department of Anthropology, University of Washington, Seattle, Washington, USA Center for Studies in Demography and Ecology, University of Washington, Seattle, Washington, USA.
authors.forename: Dan T A
authors.initials: DT
authors.lastname: Eisenberg
authors.affiliation: Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Epidemiology Unit, The Danish Aging Research Center and The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
authors.forename: Inge
authors.initials: I
authors.lastname: Petersen
authors.affiliation: Epidemiology Unit, Hebrew University-Hadassah School of Public Health and Community Medicine, Jerusalem, Israel.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Kark
authors.affiliation: Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Utz
authors.initials: U
authors.lastname: Herbig
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington, USA Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Alex P
authors.initials: AP
authors.lastname: Reiner
authors.affiliation: Department of Geriatrics, Universite de Lorraine INSERM U961, Nancy, France.
authors.forename: Athanase
authors.initials: A
authors.lastname: Benetos
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors.forename: Veryan
authors.initials: V
authors.lastname: Codd
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.affiliation: Epidemiology Unit, Hebrew University-Hadassah School of Public Health and Community Medicine, Jerusalem, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Sinnreich
authors.affiliation: Epidemiology Unit, The Danish Aging Research Center and The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark Department of Clinical Genetics, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.affiliation: Department of Cardiology, Hadassah University Medical Center, Jerusalem, Israel.
authors.forename: Hisham
authors.initials: H
authors.lastname: Nassar
authors.affiliation: Population Sciences Branch of the National Heart, Lung and Blood Institute, Bethesda, Maryland, USA The Framingham Heart Study, Framingham, Massachusetts, USA.
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Population Sciences Branch of the National Heart, Lung and Blood Institute, Bethesda, Maryland, USA The Framingham Heart Study, Framingham, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK Department of Dermatology, West Herts NHS Trust, Herts, UK.
authors.forename: Veronique
authors.initials: V
authors.lastname: Bataille
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington, USA.
authors.forename: Annette L
authors.initials: AL
authors.lastname: Fitzpatrick
authors.affiliation: Center for Cardiovascular Health, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Center for Cardiovascular Health, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Berenson
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Tishkoff
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, San Diego, California, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.affiliation: Epidemiology Unit, The Danish Aging Research Center and The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark.
authors.forename: Kirsten Ohm
authors.initials: KO
authors.lastname: Kyvik
authors.affiliation: Institute of Public Health, Environmental Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Christine
authors.initials: C
authors.lastname: Dalgård
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.affiliation: Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Abraham
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authors.lastname: Aviv
mesh_terms: D000483:Alleles; D002352:Carrier Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D007962:Leukocytes / Q000166:cytology*; D008545:Melanoma / Q000097:blood / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D016615:Telomere / Q000235:genetics; D059505:Telomere Homeostasis / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C574006:DCAF4 protein, human
keywords: Complex traits; Telomere; cancer: skin; melanoma