Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Daniel L. McCartney(Edinburgh Cancer Research), Josine L. Min(University of Bristol), Rebecca C. Richmond(University of Bristol), Ake T. Lu(University of California, Los Angeles), Maria Sobczyk(University of Bristol), Gail Davies(University of Edinburgh), Linda Broer(Erasmus MC), Xiuqing Guo(UCLA Medical Center), Ayoung Jeong(Swiss Tropical and Public Health Institute), Jeesun Jung(National Institute on Alcohol Abuse and Alcoholism), Silva Kasela(University of Tartu), Şeyma Katrinli(Emory University), Pei‐Lun Kuo(National Institute on Aging), Pamela R. Matías‐García(Helmholtz Zentrum München), Pashupati P. Mishra(Tampere University), Marianne Nygaard(University of Southern Denmark), Teemu Palviainen(University of Helsinki), Amit Patki(University of Alabama at Birmingham), Laura M. Raffield(University of North Carolina at Chapel Hill), Scott M. Ratliff(University of Michigan), Tom G. Richardson(University of Bristol), Oliver Robinson(MRC Centre for Environment and Health), Mette Soerensen(University of Southern Denmark), Dianjianyi Sun(Peking University), Pei-Chien Tsai(Chang Gung University), Matthijs D. van der Zee(Vrije Universiteit Amsterdam), Rosie M. Walker(Edinburgh Cancer Research), Xiaochuan Wang(Cancer Council Victoria), Yunzhang Wang(Karolinska Institutet), Rui Xia(Brown Foundation), Zongli Xu(Triangle), Jie Yao(UCLA Medical Center), Wei Zhao(University of Michigan), Adolfo Correa(Jackson Memorial Hospital), Eric Boerwinkle(The University of Texas Health Science Center at Houston), Pierre‐Antoine Dugué(The University of Melbourne), Peter Durda(University of Vermont), Hannah R. Elliott(University of Bristol), Christian Gieger(Helmholtz Zentrum München), Eco J. C. de Geus(Vrije Universiteit Amsterdam), Sarah E. Harris(University of Edinburgh), Gibran Hemani(University of Bristol), Medea Imboden(Swiss Tropical and Public Health Institute), Mika Kähönen(Tampere University Hospital), Sharon L. R. Kardia(University of Michigan), Jacob K. Kresovich(Triangle), Shengxu Li(Children's Minnesota), Kathryn L. Lunetta, Massimo Mangino(King's College London), Dan Mason(Bradford Teaching Hospitals NHS Foundation Trust), Andrew M. McIntosh(University of Edinburgh), Jonas Mengel‐From(University of Southern Denmark), Ann Zenobia Moore(National Institute on Aging), Joanne M. Murabito(Boston University), Miina Ollikainen(University of Helsinki), James S. Pankow(University of Minnesota), Nancy L. Pedersen(Karolinska Institutet), Annette Peters(Helmholtz Zentrum München), Silvia Polidoro(MRC Centre for Environment and Health), David J. Porteous(Edinburgh Cancer Research), Olli T. Raitakari(University of Turku), Stephen S. Rich(University of Virginia), Dale P. Sandler(Triangle), Elina Sillanpää(University of Helsinki), Alicia K. Smith(Emory University), Melissa C. Southey(The University of Melbourne), Konstantin Strauch(Johannes Gutenberg University Mainz), Hemant K. Tiwari(University of Alabama at Birmingham), Toshiko Tanaka(National Institute on Aging), Therese Tillin(MRC Unit for Lifelong Health and Ageing), André G. Uitterlinden(Erasmus MC), David Van Den Berg(University of Southern California), Jenny van Dongen(Vrije Universiteit Amsterdam), James G. Wilson(Beth Israel Deaconess Medical Center), John Wright(Bradford Teaching Hospitals NHS Foundation Trust), İdil Yet(King's College London), Donna K. Arnett(University of Kentucky), Stefania Bandinelli(Azienda Usl Toscana Centro), Jordana T. Bell(King's College London), Alexandra M. Binder(Hawaii Pacific University), Dorret I. Boomsma(Vrije Universiteit Amsterdam), Wei Chen(Tulane University), Kaare Christensen(University of Southern Denmark), Karen N. Conneely(Emory University), Paul Elliott(MRC Centre for Environment and Health), Luigi Ferrucci(National Institute on Aging), Myriam Fornage(Brown Foundation), Sara Hägg(Karolinska Institutet), Caroline Hayward(Institute of Genetics and Cancer), Marguerite M Irvin(University of Alabama at Birmingham), Jaakko Kaprio(University of Helsinki), Deborah A. Lawlor(University of Bristol), Terho Lehtimäki(Tampere University), Falk W. Lohoff(National Institute on Alcohol Abuse and Alcoholism), Lili Milani(University of Tartu), Roger L. Milne(The University of Melbourne), Nicole Probst‐Hensch(Swiss Tropical and Public Health Institute), Alex P. Reiner(University of Washington), Beate Ritz(University of California, Los Angeles), Jerome I. Rotter(UCLA Medical Center), Jennifer A. Smith(University of Michigan), Jack A. Taylor(Triangle), Joyce B. J. van Meurs(Erasmus MC), Paolo Vineis(MRC Centre for Environment and Health), Mélanie Waldenberger(Helmholtz Zentrum München), Ian J. Deary(University of Edinburgh), Caroline L. Relton(University of Bristol), Steve Horvath(University of California, Los Angeles), Riccardo E. Marioni(Edinburgh Cancer Research)
Genome biology
June 29, 2021
10.1186/s13059-021-02398-9
Cited by 299Open Access
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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.

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