DCAF4, a novel gene associated with leucocyte telomere length

Massimo Mangino; Lene Christiansen; Rivka Stone; Steven C Hunt; Kent Horvath; Dan T A Eisenberg; Masayuki Kimura; Inge Petersen; Jeremy D Kark; Utz Herbig; Alex P Reiner; Athanase Benetos; Veryan Codd; Dale R Nyholt; Ronit Sinnreich; Kaare Christensen; Hisham Nassar; Shih-Jen Hwang; Daniel Levy; Veronique Bataille; Annette L Fitzpatrick; Wei Chen; Gerald S Berenson; Nilesh J Samani; Nicholas G Martin; Sarah Tishkoff; Nicholas J Schork; Kirsten Ohm Kyvik; Christine Dalgård; Timothy D Spector; Abraham Aviv

doi:10.1136/jmedgenet-2014-102681

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DCAF4, a novel gene associated with leucocyte telomere length

Journal article

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DCAF4, a novel gene associated with leucocyte telomere length

Massimo Mangino, Lene Christiansen, Rivka Stone, Steven C Hunt, Kent Horvath, Dan T A Eisenberg, Masayuki Kimura, Inge Petersen, Jeremy D Kark, Utz Herbig, …

Journal of medical genetics, Vol.52(3), pp.157-162

03/2015

DOI: https://doi.org/10.1136/jmedgenet-2014-102681

PMCID: PMC4345921

PMID: 25624462

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.

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Title: DCAF4, a novel gene associated with leucocyte telomere length
Creators: Massimo Mangino - National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St. Thomas’ Foundation Trust, London, UK
Lene Christiansen - Department of Clinical Genetics, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
Rivka Stone - Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA
Steven C Hunt - Cardiovascular Genetics Division, Department of Medicine, University of Utah, Salt Lake City, Utah, USA
Kent Horvath - Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA
Dan T A Eisenberg - Center for Studies in Demography and Ecology, University of Washington, Seattle, Washington, USA
Masayuki Kimura - Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA
Inge Petersen - Epidemiology Unit, The Danish Aging Research Center and The Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark
Jeremy D Kark - Epidemiology Unit, Hebrew University-Hadassah School of Public Health and Community Medicine, Jerusalem, Israel
Utz Herbig - Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA
Alex P Reiner - Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
Athanase Benetos - Department of Geriatrics, Universite de Lorraine INSERM U, Nancy, France
Veryan Codd - National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
Dale R Nyholt - QIMR Berghofer Medical Research Institute, Brisbane, Australia
Ronit Sinnreich - Epidemiology Unit, Hebrew University-Hadassah School of Public Health and Community Medicine, Jerusalem, Israel
Kaare Christensen - Department of Clinical Genetics, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
Hisham Nassar - Department of Cardiology, Hadassah University Medical Center, Jerusalem, Israel
Shih-Jen Hwang - The Framingham Heart Study, Framingham, Massachusetts, USA
Daniel Levy - The Framingham Heart Study, Framingham, Massachusetts, USA
Veronique Bataille - Department of Dermatology, West Herts NHS Trust, Herts, UK
Annette L Fitzpatrick - Department of Epidemiology, University of Washington, Seattle, Washington, USA
Wei Chen - Center for Cardiovascular Health, Tulane University, New Orleans, Louisiana, USA
Gerald S Berenson - Center for Cardiovascular Health, Tulane University, New Orleans, Louisiana, USA
Nilesh J Samani - National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
Nicholas G Martin - QIMR Berghofer Medical Research Institute, Brisbane, Australia
Sarah Tishkoff - Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Nicholas J Schork - Department of Molecular and Experimental Medicine, The Scripps Research Institute, San Diego, California, USA
Kirsten Ohm Kyvik - Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark
Christine Dalgård - Institute of Public Health, Environmental Medicine, University of Southern Denmark, Odense, Denmark
Timothy D Spector - Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
Abraham Aviv - Center of Human Development and Aging, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA
Publication Details: Journal of medical genetics, Vol.52(3), pp.157-162
Date published: 03/2015
Academic Unit: Pediatrics - Developmental-Behavioral Pediatrics (NJMS); Cancer Center (NJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031654017804646