Genome Biology (Jun 2021)
Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging
- Daniel L. McCartney,
- Josine L. Min,
- Rebecca C. Richmond,
- Ake T. Lu,
- Maria K. Sobczyk,
- Gail Davies,
- Linda Broer,
- Xiuqing Guo,
- Ayoung Jeong,
- Jeesun Jung,
- Silva Kasela,
- Seyma Katrinli,
- Pei-Lun Kuo,
- Pamela R. Matias-Garcia,
- Pashupati P. Mishra,
- Marianne Nygaard,
- Teemu Palviainen,
- Amit Patki,
- Laura M. Raffield,
- Scott M. Ratliff,
- Tom G. Richardson,
- Oliver Robinson,
- Mette Soerensen,
- Dianjianyi Sun,
- Pei-Chien Tsai,
- Matthijs D. van der Zee,
- Rosie M. Walker,
- Xiaochuan Wang,
- Yunzhang Wang,
- Rui Xia,
- Zongli Xu,
- Jie Yao,
- Wei Zhao,
- Adolfo Correa,
- Eric Boerwinkle,
- Pierre-Antoine Dugué,
- Peter Durda,
- Hannah R. Elliott,
- Christian Gieger,
- The Genetics of DNA Methylation Consortium,
- Eco J. C. de Geus,
- Sarah E. Harris,
- Gibran Hemani,
- Medea Imboden,
- Mika Kähönen,
- Sharon L. R. Kardia,
- Jacob K. Kresovich,
- Shengxu Li,
- Kathryn L. Lunetta,
- Massimo Mangino,
- Dan Mason,
- Andrew M. McIntosh,
- Jonas Mengel-From,
- Ann Zenobia Moore,
- Joanne M. Murabito,
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,
- Miina Ollikainen,
- James S. Pankow,
- Nancy L. Pedersen,
- Annette Peters,
- Silvia Polidoro,
- David J. Porteous,
- Olli Raitakari,
- Stephen S. Rich,
- Dale P. Sandler,
- Elina Sillanpää,
- Alicia K. Smith,
- Melissa C. Southey,
- Konstantin Strauch,
- Hemant Tiwari,
- Toshiko Tanaka,
- Therese Tillin,
- Andre G. Uitterlinden,
- David J. Van Den Berg,
- Jenny van Dongen,
- James G. Wilson,
- John Wright,
- Idil Yet,
- Donna Arnett,
- Stefania Bandinelli,
- Jordana T. Bell,
- Alexandra M. Binder,
- Dorret I. Boomsma,
- Wei Chen,
- Kaare Christensen,
- Karen N. Conneely,
- Paul Elliott,
- Luigi Ferrucci,
- Myriam Fornage,
- Sara Hägg,
- Caroline Hayward,
- Marguerite Irvin,
- Jaakko Kaprio,
- Deborah A. Lawlor,
- Terho Lehtimäki,
- Falk W. Lohoff,
- Lili Milani,
- Roger L. Milne,
- Nicole Probst-Hensch,
- Alex P. Reiner,
- Beate Ritz,
- Jerome I. Rotter,
- Jennifer A. Smith,
- Jack A. Taylor,
- Joyce B. J. van Meurs,
- Paolo Vineis,
- Melanie Waldenberger,
- Ian J. Deary,
- Caroline L. Relton,
- Steve Horvath,
- Riccardo E. Marioni
Affiliations
- Daniel L. McCartney
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh
- Josine L. Min
- MRC Integrative Epidemiology Unit University of Bristol
- Rebecca C. Richmond
- MRC Integrative Epidemiology Unit University of Bristol
- Ake T. Lu
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles
- Maria K. Sobczyk
- MRC Integrative Epidemiology Unit University of Bristol
- Gail Davies
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh
- Linda Broer
- Department of Internal Medicine, Erasmus MC
- Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Ayoung Jeong
- Swiss Tropical and Public Health Institute
- Jeesun Jung
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health
- Silva Kasela
- Estonian Genome Centre, Institute of Genomics, University of Tartu
- Seyma Katrinli
- Department of Gynecology and Obstetrics, Emory University School of Medicine
- Pei-Lun Kuo
- Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging
- Pamela R. Matias-Garcia
- Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
- Pashupati P. Mishra
- Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University
- Marianne Nygaard
- Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark
- Teemu Palviainen
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki
- Amit Patki
- Department of Biostatistics, University of Alabama at Birmingham
- Laura M. Raffield
- Department of Genetics, University of North Carolina at Chapel Hill
- Scott M. Ratliff
- Department of Epidemiology, School of Public Health, University of Michigan
- Tom G. Richardson
- MRC Integrative Epidemiology Unit University of Bristol
- Oliver Robinson
- MRC Centre for Environment and Health, School of Public Health, Imperial College London
- Mette Soerensen
- Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark
- Dianjianyi Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center
- Pei-Chien Tsai
- Department of Twin Research and Genetic Epidemiology, King’s College London
- Matthijs D. van der Zee
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Rosie M. Walker
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh
- Xiaochuan Wang
- Cancer Epidemiology Division, Cancer Council Victoria
- Yunzhang Wang
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Rui Xia
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston
- Zongli Xu
- National Institute of Environmental Health Sciences
- Jie Yao
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Wei Zhao
- Department of Epidemiology, School of Public Health, University of Michigan
- Adolfo Correa
- Department of Medicine, University of Mississippi Medical Center
- Eric Boerwinkle
- School of Public Health, University of Texas Health Science Center at Houston
- Pierre-Antoine Dugué
- Cancer Epidemiology Division, Cancer Council Victoria
- Peter Durda
- Department of Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont
- Hannah R. Elliott
- MRC Integrative Epidemiology Unit University of Bristol
- Christian Gieger
- Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
- The Genetics of DNA Methylation Consortium
- Genetics of DNA methylation Consortium
- Eco J. C. de Geus
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Sarah E. Harris
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh
- Gibran Hemani
- MRC Integrative Epidemiology Unit University of Bristol
- Medea Imboden
- Swiss Tropical and Public Health Institute
- Mika Kähönen
- Department of Clinical Physiology, Tampere University Hospital, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University
- Sharon L. R. Kardia
- Department of Epidemiology, School of Public Health, University of Michigan
- Jacob K. Kresovich
- National Institute of Environmental Health Sciences
- Shengxu Li
- Children’s Minnesota Research Institute, Children’s Minnesota
- Kathryn L. Lunetta
- Department of Biostatistics, Boston University School of Public Health
- Massimo Mangino
- Department of Twin Research and Genetic Epidemiology, King’s College London
- Dan Mason
- Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust
- Andrew M. McIntosh
- Division of Psychiatry, University of Edinburgh
- Jonas Mengel-From
- Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark
- Ann Zenobia Moore
- Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging
- Joanne M. Murabito
- Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- TOPMed Data Coordinating Center, Genetic Analysis Center, Department of Biostatistics, University of Washington
- Miina Ollikainen
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki
- James S. Pankow
- Division of Epidemiology and Community Health, University of Minnesota
- Nancy L. Pedersen
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
- Silvia Polidoro
- MRC Centre for Environment and Health, School of Public Health, Imperial College London
- David J. Porteous
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh
- Olli Raitakari
- Centre for Population Health Research, University of Turku and Turku University Hospital
- Stephen S. Rich
- Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia
- Dale P. Sandler
- National Institute of Environmental Health Sciences
- Elina Sillanpää
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki
- Alicia K. Smith
- Department of Gynecology and Obstetrics, Emory University School of Medicine
- Melissa C. Southey
- Cancer Epidemiology Division, Cancer Council Victoria
- Konstantin Strauch
- Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
- Hemant Tiwari
- Department of Biostatistics, University of Alabama at Birmingham
- Toshiko Tanaka
- Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging
- Therese Tillin
- MRC Unit for Lifelong Health and Ageing at UCL
- Andre G. Uitterlinden
- Department of Internal Medicine, Erasmus MC
- David J. Van Den Berg
- Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine of USC, University of Southern California
- Jenny van Dongen
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- James G. Wilson
- Division of Cardiology, Beth Israel Deaconess Medical Center
- John Wright
- Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust
- Idil Yet
- Department of Twin Research and Genetic Epidemiology, King’s College London
- Donna Arnett
- Deans Office, College of Public Health, University of Kentucky
- Stefania Bandinelli
- Geriatric Unit, Azienda Sanitaria Toscana Centro
- Jordana T. Bell
- Department of Twin Research and Genetic Epidemiology, King’s College London
- Alexandra M. Binder
- Department of Epidemiology, Fielding School of Public Health, University of California
- Dorret I. Boomsma
- Department of Biological Psychology, Vrije Universiteit Amsterdam
- Wei Chen
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University
- Kaare Christensen
- Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark
- Karen N. Conneely
- Department of Human Genetics, Emory University School of Medicine
- Paul Elliott
- MRC Centre for Environment and Health, School of Public Health, Imperial College London
- Luigi Ferrucci
- Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging
- Myriam Fornage
- Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston
- Sara Hägg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh
- Marguerite Irvin
- Dept of Epidemiology, University of Alabama at Birmingham
- Jaakko Kaprio
- Institute for Molecular Medicine Finland, FIMM, HiLIFE, University of Helsinki
- Deborah A. Lawlor
- MRC Integrative Epidemiology Unit University of Bristol
- Terho Lehtimäki
- Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University
- Falk W. Lohoff
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health
- Lili Milani
- Estonian Genome Centre, Institute of Genomics, University of Tartu
- Roger L. Milne
- Cancer Epidemiology Division, Cancer Council Victoria
- Nicole Probst-Hensch
- Swiss Tropical and Public Health Institute
- Alex P. Reiner
- Department of Epidemiology, University of Washington
- Beate Ritz
- Department of Epidemiology, Fielding School of Public Health, University of California
- Jerome I. Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Jennifer A. Smith
- Department of Epidemiology, School of Public Health, University of Michigan
- Jack A. Taylor
- National Institute of Environmental Health Sciences
- Joyce B. J. van Meurs
- Department of Internal Medicine, Erasmus MC
- Paolo Vineis
- MRC Centre for Environment and Health, School of Public Health, Imperial College London
- Melanie Waldenberger
- Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health
- Ian J. Deary
- Lothian Birth Cohorts, Department of Psychology, University of Edinburgh
- Caroline L. Relton
- MRC Integrative Epidemiology Unit University of Bristol
- Steve Horvath
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles
- Riccardo E. Marioni
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh
- DOI
- https://doi.org/10.1186/s13059-021-02398-9
- Journal volume & issue
-
Vol. 22,
no. 1
pp. 1 – 25
Abstract
Abstract Background Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
Keywords
