Dataset Information

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

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.

SUBMITTER: McCartney DL

PROVIDER: S-EPMC8243879 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

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

McCartney Daniel L DL Min Josine L JL Richmond Rebecca C RC Lu Ake T AT Sobczyk Maria K MK Davies Gail G Broer Linda L Guo Xiuqing X Jeong Ayoung A Jung Jeesun J Kasela Silva S Katrinli Seyma S Kuo Pei-Lun PL Matias-Garcia Pamela R PR Mishra Pashupati P PP Nygaard Marianne M Palviainen Teemu T Patki Amit A Raffield Laura M LM Ratliff Scott M SM Richardson Tom G TG Robinson Oliver O Soerensen Mette M Sun Dianjianyi D Tsai Pei-Chien PC van der Zee Matthijs D MD Walker Rosie M RM Wang Xiaochuan X Wang Yunzhang Y Xia Rui R Xu Zongli Z Yao Jie J Zhao Wei W Correa Adolfo A Boerwinkle Eric E Dugué Pierre-Antoine PA Durda Peter P Elliott Hannah R HR Gieger Christian C de Geus Eco J C EJC Harris Sarah E SE Hemani Gibran G Imboden Medea M Kähönen Mika M Kardia Sharon L R SLR Kresovich Jacob K JK Li Shengxu S Lunetta Kathryn L KL Mangino Massimo M Mason Dan D McIntosh Andrew M AM Mengel-From Jonas J Moore Ann Zenobia AZ Murabito Joanne M JM Ollikainen Miina M Pankow James S JS Pedersen Nancy L NL Peters Annette A Polidoro Silvia S Porteous David J DJ Raitakari Olli O Rich Stephen S SS Sandler Dale P DP Sillanpää Elina E Smith Alicia K AK Southey Melissa C MC Strauch Konstantin K Tiwari Hemant H Tanaka Toshiko T Tillin Therese T Uitterlinden Andre G AG Van Den Berg David J DJ van Dongen Jenny J Wilson James G JG Wright John J Yet Idil I Arnett Donna D Bandinelli Stefania S Bell Jordana T JT Binder Alexandra M AM Boomsma Dorret I DI Chen Wei W Christensen Kaare K Conneely Karen N KN Elliott Paul P Ferrucci Luigi L Fornage Myriam M Hägg Sara S Hayward Caroline C Irvin Marguerite M Kaprio Jaakko J Lawlor Deborah A DA Lehtimäki Terho T Lohoff Falk W FW Milani Lili L Milne Roger L RL Probst-Hensch Nicole N Reiner Alex P AP Ritz Beate B Rotter Jerome I JI Smith Jennifer A JA Taylor Jack A JA van Meurs Joyce B J JBJ Vineis Paolo P Waldenberger Melanie M Deary Ian J IJ Relton Caroline L CL Horvath Steve S Marioni Riccardo E RE

Genome biology 20210629 1

<h4>Background</h4>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.<h4>Results</h4>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) ...[more]

PMID: 34187551

Similar Datasets

Project description:BackgroundIncreased epigenetic age acceleration (EAA) in survivors of childhood cancer is associated with specific treatment exposures, unfavorable health behaviors, and presence of certain chronic health conditions. To better understand inter-individual variability, we investigated the genetic basis underlying EAA.MethodsGenome-wide association studies of EAA based on multiple epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) were performed. MethylationEPIC BeadChip array and whole-genome sequencing data were generated with blood-derived DNA from participants in the St. Jude Lifetime Cohort Study (discovery: 2138 pre-existing and 502 newly generated data, all survivors; exploratory: 282 community controls). Linear regression models were fit for each epigenetic age against the allelic dose of each genetic variant, adjusting for age at sampling, sex, and cancer treatment exposures. Fixed-effects meta-analysis was used to combine summary statistics from two discovery data sets. LD (Linkage disequilibrium) score regression was used to estimate single-nucleotide polymorphism (SNP)-based heritability.ResultsFor EAA-Horvath, a genome-wide significant association was mapped to the SELP gene with the strongest SNP rs732314 (meta-GWAS: β=0.57, P=3.30×10-11). Moreover, the stratified analysis of the association between rs732314 and EAA-Horvath showed a substantial heterogeneity between children and adults (meta-GWAS: β=0.97 vs. 0.51, I2=73.1%) as well as between survivors with and without chest/abdominal/pelvic-RT exposure (β=0.64 vs. 0.31, I2=66.3%). For EAA-Hannum, an association was mapped to the HLA locus with the strongest SNP rs28366133 (meta-GWAS: β=0.78, P=3.78×10-11). There was no genome-wide significant hit for EAA-PhenoAge or EAA-GrimAge. Interestingly, among community controls, rs732314 was associated with EAA-Horvath (β=1.09, P=5.43×10-5), whereas rs28366133 was not associated with EAA-Hannum (β=0.21, P=0.49). The estimated heritability was 0.33 (SE=0.20) for EAA-Horvath and 0.17 (SE=0.23) for EAA-Hannum, but close to zero for EAA-PhenoAge and EAA-GrimAge.ConclusionsWe identified novel genetic variants in the SELP gene and HLA region associated with EAA-Horvath and EAA-Hannum, respectively, among survivors of childhood cancer. The new genetic variants in combination with other replicated known variants can facilitate the identification of survivors at higher risk in developing accelerated aging and potentially inform drug targets for future intervention strategies among vulnerable survivors.

Project description:BackgroundFibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined based on interindividual differences in DNA methylation at cytosine-phosphate-guanine (CpG) sites and vice versa.ObjectivesTo perform an EWAS to examine an association between blood DNA methylation levels and circulating fibrinogen levels to better understand its biological and pathophysiological actions.MethodsWe performed an epigenome-wide association study of circulating fibrinogen levels in 18 037 White, Black, American Indian, and Hispanic participants, representing 14 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. Circulating leukocyte DNA methylation was measured using the Illumina 450K array in 12 904 participants and using the EPIC array in 5133 participants. In each study, an epigenome-wide association study of fibrinogen was performed using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without CRP adjustment to examine the role of inflammation.ResultsWe identified 208 and 87 significant CpG sites associated with fibrinogen levels from the 450K (p < 1.03 × 10-7) and EPIC arrays (p < 5.78 × 10-8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. The examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations of all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant.ConclusionWe identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.

Dataset Information

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

Background

Results

Conclusion

Publications

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

Similar Datasets

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