Whole-genome profiling of age- and sex-associated DNA methylation signatures in human plasma cell-free DNA

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Age and sex significantly impact DNA methylation patterns, however, existing datasets typically include only a subset of methylation sites in the human genome, hindering our thorough understanding. We recruited 98 generally healthy adults aged from 22 to 77 and investigated the effects of age and sex on plasma cell-free DNA (cfDNA) methylation through whole-genome bisulfite sequencing (WGBS) and association analysis. Here we show 3,047 age-associated and 1,053 sex-associated CpGs on autosomes, corresponding to 1,587 and 324 genes, respectively. To the best of our knowledge, many of these CpGs are newly discovered to be age- and sex-related at the DNA methylation level. The discovered sex-differential cfDNA methylation patterns on the X chromosome are related to XCI status. Besides, a cfDNA epigenetic clock comprising 125 CpGs is developed, demonstrating relatively high accuracy in predicting chronological age. Tissue-of-origin analysis reveals that cfDNA derived from monocytes/macrophages, granulocytes, and hepatocytes is associated with age and sex. Several individuals with abnormal cfDNA proportions of some specific cell types are found to have individual health problems. Our discovered CpGs and genes help to explain age-related and sex-biased diseases such as psychiatric disorders, diabetes, and autoimmune diseases, and we demonstrate the potential of cfDNA methylation signatures as very promising biomarkers for health monitoring for the general population. Aging is a complex biological process shaping disease risks. Meanwhile, the influence of sex differences is still underexplored. There are various influencing factors, including modifications on DNA called DNA methylation which are important for gene regulations. In this study, we explore the age-related changes and sex-related differences in DNA methylation in blood samples, by recruiting 98 generally healthy adults aged from 22 to 77. Based on DNA methylation sequencing, we identify two sets of genes that help to explain some age-related and sex-biased diseases. We also develop a methylation aging clock for estimating biological age. Moreover, we demonstrate the potential of methylation signatures as very promising biomarkers for health monitoring, as they contain health risk information from immune cells and tissue injuries. Chen et al. comprehensively depict the effects of age and sex on blood plasma cfDNA methylation through whole-genome bisulfite sequencing (WGBS). They display cfDNA methylation signatures as promising biomarkers in aging and health monitoring.

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