Genetic and Environmental Causes of Variation in the Difference Between Biological Age Based on DNA Methylation and Chronological Age for Middle-Aged Women

Abstract

The disease-and mortality-related difference between biological age based on DNA methylation and chronological age ( age) has been found to have approximately 40% heritability by assuming that the familial correlation is only explained by additive genetic factors. We calculated two different age measures for 132 middle-aged female twin pairs (66 monozygotic and 66 dizygotic twin pairs) and their 215 sisters using DNA methylation data measured by the Infinium HumanMethylation450 BeadChip arrays. For each age measure, and their combined measure, we estimated the familial correlation for MZ, DZ and sibling pairs using the multivariate normal model for pedigree analysis. We also pooled our estimates with those from a former study to estimate weighted average correlations. For both age measures, there was familial correlation that varied across different types of relatives. No evidence of a difference was found between the MZ and DZ pair correlations, or between the DZ and sibling pair correlations. The only difference was between the MZ and sibling pair correlations (p < .01), and there was marginal evidence that the MZ pair correlation was greater than twice the sibling pair correlation (p < .08). For weighted average correlation, there was evidence that the MZ pair correlation was greater than the DZ pair correlation (p < .03), and marginally greater than twice the sibling pair correlation (p < .08). The varied familial correlation of age is not explained by additive genetic factors alone, implying the existence of shared non-genetic factors explaining variation in age for middle-aged women.Keywords: twin family study, DNA methylation, age, familial correlation, heritability DNA methylation, one type of epigenetic modification mainly occurring at the CpG dinucleotide, is associated with the regulation of gene expression. DNA methylation does not remain constant over time (Fraga et al., 2005;Wong et al., 2010), even in early infancy (Martino et al., 2013). Previous studies suggest there are age-sensitive sites of DNA methylation (Alisch et al., 2012;Bell et al., 2012;Bocklandt et al., 2011;Florath et al., 2014;Hannum et al., 2013;Johansson et al., 2013;Rakyan et al., 2010).Six studies have developed algorithms that use DNA methylation to predict chronological age (Bocklandt et al., 2011;Florath et al., 2014;Hannum et al., 2013;Horvath, 2013;Koch & Wagner, 2011;Weidner et al., 2014). The predicted value is regarded as the methylation-based biological age (m age ) for the corresponding tissue. In particular, Hannum and colleagues developed an age predictor based on methylation levels at 71 probes from the Illumina 450K Methylation arrays using data from whole blood (Hannum et al., 2013 Methylation arrays using data from multiple tissues and cell types was developed by Horvath (2013).Methylation age acceleration index, defined as age = m age -chronological age (Horvath, 2013), represents the inconsistency between methylation-based biological age and chronological age. There is now evidence that both the age measures f...

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