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

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.