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.

Details

Title
Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging
Author
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; Silva Kasela; Katrinli, Seyma; Pei-Lun Kuo; 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; Pei-Chien Tsai; Matthijs D. van der Zee; Walker, Rosie M; Wang, Xiaochuan; Wang, Yunzhang; Xia, Rui; Xu, Zongli; Yao, Jie; Zhao, Wei; Correa, Adolfo; Boerwinkle, Eric; Pierre-Antoine Dugué; Durda, Peter; Elliott, Hannah R; Gieger, Christian; of DNA Methylation Consortium; Eco J. C. de Geus; Harris, Sarah E; Gibran Hemani; 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; Ann Zenobia Moore; 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; David J. Van Den Berg; Jenny van Dongen; 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; Joyce B. J. van Meurs; Vineis, Paolo; Waldenberger, Melanie; Deary, Ian J; Relton, Caroline L; Horvath, Steve; Marioni, Riccardo E  VIAFID ORCID Logo 
Pages
1-25
Section
Research
Publication year
2021
Publication date
2021
Publisher
BioMed Central
ISSN
14747596
e-ISSN
1474760X
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1186/s13059-021-02398-9
ProQuest document ID
2553258919
Copyright
© 2021. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.