DNA methylation and all-cause mortality in middle-aged and elderly Danish twins

Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG methylation and mortality in a population of 435 monozygotic twin pairs from three Danish twin studies. The participants were aged 55–90 at the time of blood sampling and were followed for up to 20 years. We validated our results by comparison with results from a British and a Swedish cohort, as well as results from the literature. We identified 2806 CpG sites associated with mortality (false discovery rate ( FDR ) < 0.05 ), of which 24 had an association p-value below 10 − 7 . This was confirmed by intra-pair comparison controlling for confounding effects. Eight of the 24 top sites could be validated in independent datasets or confirmed by previous studies. For all these eight sites, hypomethylation was associated with poor survival prognosis, and seven showed monozygotic correlations above 35%, indicating a potential moderate to strong heritability, but leaving room for substantial shared or unique environmental effects. We also set up a predictor for mortality using least absolute shrinkage and selection operator (LASSO) regression. The predictor showed good performance on the Danish data under cross-validation, but did not perform very well in independent samples

Placenta Imaging Workshop 2018 report:Multiscale and multimodal approaches

The Centre for Medical Image Computing (CMIC) at University College London (UCL) hosted a two-day workshop on placenta imaging on April 12th and 13th 2018. The workshop consisted of 10 invited talks, 3 contributed talks, a poster session, a public interaction session and a panel discussion about the future direction of placental imaging. With approximately 50 placental researchers in attendance, the workshop was a platform for engineers, clinicians and medical experts in the field to network and exchange ideas. Attendees had the chance to explore over 20 posters with subjects ranging from the movement of blood within the placenta to the efficient segmentation of fetal MRI using deep learning tools. UCL public engagement specialists also presented a poster, encouraging attendees to learn more about how to engage patients and the public with their research, creating spaces for mutual learning and dialogue

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

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.Peer reviewe

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

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.</p

Untangling the Genetics of Human Longevity—A Challenging Quest

Human average life expectancy in developed countries has increased dramatically in the last century, a phenomenon which is potentially accompanied by a significant rise in multi-morbidity and frailty among older individuals [...

Limitations and risks of meta-analyses of longevity studies

Searching for genetic determinants of human longevity has been challenged by the rarity of data sets with large numbers of individuals who have reached extreme old age, inconsistent definitions of the phenotype, and the difficulty of defining appropriate controls. Meta-analysis - a statistical method to summarize results from different studies - has become a common tool in genetic epidemiology to accrue large sample sizes for powerful genetic association studies. In conducting a meta-analysis of studies of human longevity however, particular attention must be made to the definition of cases and controls (including their health status) and on the effect of possible confounders such as sex and ethnicity upon the genetic effect to be estimated. We will show examples of how a meta-analysis can inflate the false negative rates of genetic association studies or it can bias estimates of the association between a genetic variant and extreme longevity