Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging
Authors: McCartney Daniel L. , Min Josine L. , Richmond Rebecca C. , Lu Ake T. , Sobczyk Maria K. , Davies Gail , Broer Linda , Guo Xiuqing , Jeong Ayoung , Jung Jeesun , Kasela Silva , Katrinli Seyma , Kuo Pei-Lun , Matias-Garcia Pamela R. , Mishra Pashupati P. , Nygaard Marianne , Palviainen Teemu , Patki Amit , Raffield Laura M. , Ratliff Scott M. , Richardson Tom G. , Robinson Oliver , Soerensen Mette , Sun Dianjianyi , Tsai Pei-Chien , van der Zee Matthijs D. , Walker Rosie M. , Wang Xiaochuan , Wang Yunzhang , Xia Rui , Xu Zongli , Yao Jie , Zhao Wei , Correa Adolfo , Boerwinkle Eric , Dugué Pierre-Antoine , Durda Peter , Elliott Hannah R. , Gieger Christian ,   The Genetics of DNA Methylation Consortium, de Geus Eco J. C. , Harris Sarah E. , Hemani Gibran , Imboden Medea , Kähönen Mika , Kardia Sharon L. R. , Kresovich Jacob K. , Li Shengxu , Lunetta Kathryn L. , Mangino Massimo , Mason Dan , McIntosh Andrew M. , Mengel-From Jonas , Moore Ann Zenobia , Murabito Joanne M. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Ollikainen Miina , Pankow James S. , Pedersen Nancy L. , Peters Annette , Polidoro Silvia , Porteous David J. , Raitakari Olli , Rich Stephen S. , Sandler Dale P. , Sillanpää Elina , Smith Alicia K. , Southey Melissa C. , Strauch Konstantin , Tiwari Hemant , Tanaka Toshiko , Tillin Therese , Uitterlinden Andre G. , Van Den Berg David J. , van Dongen Jenny , Wilson James G. , Wright John , Yet Idil , Arnett Donna , Bandinelli Stefania , Bell Jordana T. , Binder Alexandra M. , Boomsma Dorret I. , Chen Wei , Christensen Kaare , Conneely Karen N. , Elliott Paul , Ferrucci Luigi , Fornage Myriam , Hägg Sara , Hayward Caroline , Irvin Marguerite , Kaprio Jaakko , Lawlor Deborah A. , Lehtimäki Terho , Lohoff Falk W. , Milani Lili , Milne Roger L. , Probst-Hensch Nicole , Reiner Alex P. , Ritz Beate , Rotter Jerome I. , Smith Jennifer A. , Taylor Jack A. , van Meurs Joyce B. J. , Vineis Paolo , Waldenberger Melanie , Deary Ian J. , Relton Caroline L. , Horvath Steve , Marioni Riccardo E. 
Published: June 2021

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.