Gender Affirming Hormone Therapy induces specific DNA methylation changes in blood

DNA methylation is an epigenetic mark that is influenced by underlying genetic profile, environment, and aging. It also plays a key role in female-specific X-chromosome silencing in mammals. In addition to X-linked DNA methylation, sex-specific methylation patterns are widespread across autosomal chromosomes and can be present from birth or arise over time. In individuals where gender identity and sex assigned at birth are markedly and consistently incongruent, as in the case of transgender people, feminization or masculinization may be sought through gender affirming hormone therapy (GAHT). In this study we profiled genome-wide DNA methylation in blood of transgender women and transgender men, before and during GAHT (6 months and 12 months into hormone treatment). We identified several thousand differentially methylated CpG sites (DMPs) in both people undergoing feminizing and masculinizing hormone therapy, the vast majority of which were progressive changes over time. Sex-specific DNA methylation patterns established in early development are largely refractory to change in association with GAHT. The small number of sex-DMPs that were affected by GAHT were those that become sex-specific during the lifetime, known as sex-and-age DMPs.