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

McCartney DL, Min JL, Richmond RC, Lu AT, Sobczyk MK, Davies G, Broer L, Guo X, Jeong A, Jung J, Kasela S, Katrinli S, Kuo PL, Matias-Garcia PR, Mishra PP, Nygaard M, Palviainen T, Patki A, Raffield LM, Ratliff SM, Richardson TG, Robinson O, Soerensen M, Sun D, Tsai PC, van der Zee MD, Walker RM, Wang X, Wang Y, Xia R, Xu Z, Yao J, Zhao W, Correa A, Boerwinkle E, Dugué PA, Durda P, Elliott HR, Gieger C, Genetics of DNA Methylation Consortium , de Geus EJC, Harris SE, Hemani G, Imboden M, Kähönen M, Kardia SLR, Kresovich JK, Li S, Lunetta KL, Mangino M, Mason D, McIntosh AM, Mengel-From J, Moore AZ, Murabito JM, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium , Ollikainen M, Pankow JS, Pedersen NL, Peters A, Polidoro S, Porteous DJ, Raitakari O, Rich SS, Sandler DP, Sillanpää E, Smith AK, Southey MC, Strauch K, Tiwari H, Tanaka T, Tillin T, Uitterlinden AG, Van Den Berg DJ, van Dongen J, Wilson JG, Wright J, Yet I, Arnett D, Bandinelli S, Bell JT, Binder AM, Boomsma DI, Chen W, Christensen K, Conneely KN, Elliott P, Ferrucci L, Fornage M, Hägg S, Hayward C, Irvin M, Kaprio J, Lawlor DA, Lehtimäki T, Lohoff FW, Milani L, Milne RL, Probst-Hensch N, Reiner AP, Ritz B, Rotter JI, Smith JA, Taylor JA, van Meurs JBJ, Vineis P, Waldenberger M, Deary IJ, Relton CL, Horvath S, Marioni RE

Genome Biol. 22 (1) 194 [2021-06-29; online 2021-06-29]

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. 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. This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

NGI Uppsala (SNP&SEQ Technology Platform)

National Genomics Infrastructure

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PubMed 34187551

DOI 10.1186/s13059-021-02398-9

Crossref 10.1186/s13059-021-02398-9

pii: 10.1186/s13059-021-02398-9
pmc: PMC8243879