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

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, Şeyma; Kuo, Pei‐Lun; Matías‐García, Pamela R.; Mishra, Pashupati P.; Nygaard, Marianne; Palviainen, Teemu; Patki, Amit; Raffield, Laura M.; Ratliff, Scott; Richardson, Tom G; Robinson, Oliver; Soerensen, Mette; Sun, Dianjianyi; Tsai, Pei-Chien; Zee, Matthijs D. van der; 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; Geus, E.J.C. de; 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.; Ollikainen, Miina; Pankow, James S.; Pedersen, Nancy L.; Peters, Annette; Polidoro, Silvia; Porteous, David J.; Raitakari, Olli T.; Rich, Stephen S.; Sandler, Dale P.; Sillanpää, Elina; Smith, Alicia K.; Southey, Melissa C.; Strauch, Konstantin; Tiwari, Hemant K.; Tanaka, Toshiko; Tillin, Therese; Uitterlinden, André G.; Berg, David J. Van Den; Dongen, Jenny van; Wilson, James G.; Wright, John; Yet, İdil; Arnett, Donna K.; 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 R.; 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.; Meurs, Joyce B. J. van; Víneis, Paolo; Waldenberger, Mélanie; Deary, Ian J.; Relton, Caroline; Horvath, Steve; Marioni, Riccardo E.

doi:10.1101/2020.06.29.133702

Cited by 15 publications

(26 citation statements)

References 84 publications

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“…However, none of the lifespan-related traits showed a significant protective effect on COVID-19 with a severe respiratory disorder or respiratory failure, possibly due to the small case number of severe COVID-19 (Table S1). We also estimated the causal effect of genetically proxied epigenetic age acceleration on the risk of COVID-19 20 , while none of them shown to have a significant effect on COVID-19 after Bonferroni correction for 144 tests (Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

“…We also included GWAS for age acceleration measured by four epigenetic clocks, including Hannum age, Horvath age, PhenoAge, and GrimAge 20 . The epigenetic age was measured on 34,449 healthy individuals of European ancestry.…”

Section: Methodsmentioning

confidence: 99%

“…The coronavirus disease 2019 (COVID- 19), caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), first emerged in late 2019 and has led to an unprecedented global health crisis 1 . Notably, the aging population is particularly at risk of COVID-19 2 , e.g.…”

Section: Introductionmentioning

confidence: 99%

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Genetic and Phenotypic Evidence for the Causal Relationship Between Aging and COVID-19

Ying

Zhai

Pyrkov

et al. 2020

Preprint

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Epidemiological studies have revealed that the elderly and those with co-morbidities are most susceptible to COVID-19. To understand the genetic link between aging and the risk of COVID-19, we conducted a multi-instrument Mendelian randomization analysis and found that the genetic variation that leads to a longer lifespan is significantly associated with a lower risk of COVID-19 infection. The odds ratio is 0.32 (95% CI: 0.18 to 0.57; P = 1.3 × 10-4) per additional 10 years of life, and 0.62 (95% CI: 0.51 to 0.77; P = 7.2 × 10-6) per unit higher log odds of surviving to the 90th percentile age. On the other hand, there was no association between COVID-19 susceptibility and healthspan (the lifespan free of the top seven age-related morbidities). To examine the relationship at the phenotypic level, we applied various biological aging clock models and detected an association between the biological age acceleration and future incidence and severity of COVID-19 infection for all subjects as well as for the individuals free of chronic disease. Biological age acceleration was also significantly associated with the risk of death in COVID-19 patients. Our findings suggest a causal relationship between aging and COVID-19, defined by genetic variance, the rate of aging, and the burden of chronic diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Genetic and Phenotypic Evidence for the Causal Relationship Between Aging and COVID-19

Ying

Zhai

Pyrkov

et al. 2020

Preprint

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“…Data on the genetic association with alcohol use (AUDIT-C) was extracted from Kranzler et al (33). Summary statistics for these SNPs were extracted from GWASs for AgeAccelGrim and AgeAccelPheno conducted by McCartney et al (31). rs185177474 was not available in AgeAccelGrim and AgeAccelPheno summary statistics, thus rs151242810 was used as a proxy (R 2 =0.976; see Supplementary methods).N SNP=number of SNPs included in the MR analysis, CI = confidence interval.…”

Section: We Further Demonstrate a Positive Association Between Alcohomentioning

confidence: 99%

“…However, the associations between alcohol consumption levels and epigenetic ageing are complex, with studies showing positive (25), negative (17) and non-linear (26) relationships. Additionally, a recent study suggests both positive and negative genetic associations between various alcohol-related traits and epigenetic ageing using LD score regression (31).…”

Section: Introductionmentioning

confidence: 99%

Associations between alcohol use and accelerated biological ageing

Bøstrand

Vaher

Nooij

et al. 2020

Preprint

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BackgroundHarmful alcohol use is a leading cause of premature death, and is associated with age-related disease. Ageing is highly variable between individuals, and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (based on DNA methylation or brain structural measures) may be clinically relevant. Here, we investigated the relationships between alcohol phenotypes and both brain and DNA methylation age estimates.MethodsFirst, using data from UK Biobank and Generation Scotland, we tested the association between alcohol consumption (units/week) or hazardous use (AUDIT scores), and accelerated brain and epigenetic ageing in 20,258 and 8,051 individuals, respectively. Second, we used Mendelian randomization to test for a causal effect of alcohol consumption levels and alcohol use disorder (AUD) on biological ageing.ResultsAlcohol use showed a consistent positive association with higher predicted brain age (AUDIT-C: β=0.053, p=3.16×10−13; AUDIT-P: β=0.052, p=1.6×10−13; total AUDIT score: β=0.062, p=5.52×10−16; units/week: β=0.078, p=2.20×10−16), and DNA methylation GrimAge (Units/week: β=0.053, p=1.48×10− 7) and PhenoAge (Units/week: β=0.077, p=2.18×10−10). Mendelian randomization analyses revealed some evidence for a causal effect of AUD on accelerated brain ageing (β=0.272, p=0.044), and no evidence for a causal effect of alcohol consumption levels on accelerated biological ageing.ConclusionsWe provide consistent phenotypic evidence linking alcohol use with accelerated biological ageing. There is possible evidence for a causal effect of AUD on brain age, but not for any other alcohol-related trait on brain or epigenetic age acceleration. Future studies investigating the mechanisms associating alcohol use with accelerated biological ageing are warranted.

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Epidemiology, Genetics and Epigenetics of Biological Aging: One or More Aging Systems?

Gialluisi

Izzi

Gaetano

et al. 2023

Artificial Intelligence for Healthy Longevity

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

Cited by 15 publications

References 84 publications

Genetic and Phenotypic Evidence for the Causal Relationship Between Aging and COVID-19

Genetic and Phenotypic Evidence for the Causal Relationship Between Aging and COVID-19

Associations between alcohol use and accelerated biological ageing

Epidemiology, Genetics and Epigenetics of Biological Aging: One or More Aging Systems?

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