Journal Article

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

Broer, Linda, Irvin, Marguerite, Sobczyk, Maria K., Ollikainen, Miina, van Dongen, Jenny, Jung, Jeesun, Arnett, Donna, Tillin, Therese, Walker, Rosie M., Fornage, Myriam, Kasela, Silva, Probst-Hensch, Nicole, Durda, Peter, Pedersen, Nancy L., Elliott, Paul, Waldenberger, Melanie, Peters, Annette, Murabito, Joanne M., Ritz, Beate, Mengel-From, Jonas, Uitterlinden, Andre G., Boomsma, Dorret I., Yet, Idil, Kaprio, Jaakko, Hayward, Caroline, Kähönen, Mika, McCartney, Daniel L., Hemani, Gibran, Tsai, Pei-Chien, Wang, Xiaochuan, Davies, Gail, Boerwinkle, Eric, Dugué, Pierre-Antoine, McIntosh, Andrew M., Raffield, Laura M., Conneely, Karen N., Lunetta, Kathryn L., Gieger, Christian, Ferrucci, Luigi, van der Zee, Matthijs D., Zhao, Wei, Yao, Jie, Jeong, Ayoung, Matias-Garcia, Pamela R., Lawlor, Deborah A., Kuo, Pei-Lun, Smith, Alicia K., Lohoff, Falk W., Robinson, Oliver, Chen, Wei, Ratliff, Scott M., Richmond, Rebecca C., Rich, Stephen S., Southey, Melissa C., Elliott, Hannah R., Reiner, Alex P., Smith, Jennifer A., Vineis, Paolo, Horvath, Steve, Palviainen, Teemu, Moore, Ann Zenobia, Nygaard, Marianne, Richardson

2021

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adipose tissue / Adiposity - genetics / Adiposity - immunology / African Americans / Age / Aging / Aging - genetics / Aging - immunology / Animal Genetics and Genomics / Bioinformatics / Biomarkers / Biomarkers - metabolism / Biomedical and Life Sciences / Blood / C-reactive protein / C-Reactive Protein - genetics / C-Reactive Protein - immunology / CpG Islands / Deoxyribonucleic acid / DNA / DNA Methylation / Educational Status / Epigenesis, Genetic / Epigenetic clock / Epigenetics / Estimates / Evolutionary Biology / Gene loci / Genetic Loci / Genetic Markers / genome / Genome, Human / Genome-wide association studies / Genome-Wide Association Study / Genomes / Granulocytes / Granulocytes - cytology / Granulocytes - immunology / GWAS / Human Genetics / Humans / Immune response / Immunity, Innate / Leukocytes (granulocytic) / Life Sciences / lifestyle / Lipid metabolism / Lipid Metabolism - genetics / Lipid Metabolism - immunology / Longevity / Meta-analysis / Microbial Genetics and Genomics / Morbidity / Mortality / Multifactorial Inheritance / Plant Genetics and Genomics / Plasminogen Activator Inhibitor 1 - genetics / Plasminogen Activator Inhibitor 1 - immunology / Plasminogen activator inhibitors / Polygenic inheritance / Single-nucleotide polymorphism / Standard deviation / Statistics