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Research Paper|Volume 11, Issue 16|pp 5876—5894

Epigenome-wide association study of leukocyte telomere length

Yunsung Lee1, Dianjianyi Sun2,3, Anil P.S. Ori4, Ake T. Lu5, Anne Seeboth6, Sarah E. Harris7,8, Ian J. Deary7,8, Riccardo E. Marioni6,7, Mette Soerensen9,10,11, Jonas Mengel-From9,10, Jacob Hjelmborg9, Kaare Christensen9,10, James G. Wilson12,13, Daniel Levy14,15, Alex P. Reiner16, Wei Chen3, Shengxu Li17, Jennifer R. Harris1,18, Per Magnus18, Abraham Aviv19, Astanand Jugessur1,18,20, Steve Horvath5,20
  • 1Department of Genetics and Bioinformatics, Norwegian Institute of Public Health, Oslo, Norway
  • 2Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
  • 3Department of Epidemiology, Tulane University, New Orleans, LA 70118, USA
  • 4Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA 90095, USA
  • 5Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
  • 6Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  • 7Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
  • 8Department of Psychology, University of Edinburgh, Edinburgh, UK
  • 9Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense C, Denmark
  • 10Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
  • 11Center for Individualized Medicine in Arterial Diseases, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense C, Denmark
  • 12Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA
  • 13Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA 20892, USA
  • 14The Framingham Heart Study, Framingham, MA 01702, USA
  • 15Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Seattle, MD 20892, USA
  • 16Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
  • 17Children’s Minnesota Research Institute, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN 55404, USA
  • 18Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
  • 19Center of Development and Aging, New Jersey Medical School, Rutgers State University of New Jersey, Newark, NJ 07103, USA
  • 20Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
  • 21Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA
# Co-first authors
* Co-last authors
Received: June 3, 2019Accepted: August 18, 2019Published: August 26, 2019

Copyright © 2019 Lee et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY 3.0) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) – the Framingham Heart Study, the Jackson Heart Study, the Women’s Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P<1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.