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 Sobczyk, Gail Davies, Linda Broer, Xiuqing Guo, Ayoung Jeong, Jeesun Jung, Silva Kasela, Şeyma Katrinli, Pei‐Lun Kuo, Pamela R. Matías‐García, 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, 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, Miina Ollikainen, James S. Pankow, Nancy L. Pedersen, Annette Peters, Silvia Polidoro, David J. Porteous, Olli T. Raitakari, Stephen S. Rich, Dale P. Sandler, Elina Sillanpää, Alicia K. Smith, Melissa C. Southey, Konstantin Strauch, Hemant K. Tiwari, Toshiko Tanaka, Therese Tillin, André G. Uitterlinden, David Van Den Berg, Jenny van Dongen, James G. Wilson, John Wright, İdil Yet, Donna K. 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 M 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
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.