DNA methylation changes in young female adolescents with anorexia nervosa : focus on puberty related genes.

PURPOSE: Anorexia nervosa (AN) is a severe eating disorder with high morbidity that typically arises during adolescence. While genetic predisposition contributes to its development, emerging evidence highlights the role of environmental stressors and epigenetic mechanisms—particularly DNA methylation—in mediating these effects. This study aimed to investigate genome-wide DNA methylation alterations in young female adolescents with AN and functional hypogonadotropic hypogonadism, compared to healthy pubertal controls, to explore in particular potential epigenetic biomarkers of metabolic dysfunction and pubertal delay.

METHODS

Peripheral blood DNA was extracted from 10 young adolescent girls with AN and 11 age-matched healthy controls. Genome-wide DNA methylation analysis was performed using the Infinium MethylationEPIC BeadChip (850 K) array, which interrogates over 850,000 CpG sites. Differentially methylated regions (DMRs) and CpG sites were identified, followed by functional annotation. Ingenuity Pathway Analysis (IPA) was conducted to investigate the biological significance of the methylation changes.

RESULTS

A total of 87 DMRs were identified, with 69% showing hypomethylation in the AN group. These included genes such as CLU and MKRN3, involved in hypothalamic regulation and pubertal timing. Additionally, 2072 differentially methylated CpG sites were found, affecting genes linked to metabolism (e.g., LEPR, NR1H3) and puberty (e.g., GHR, DLK1). Ninety-two genes encoding zinc-finger proteins, including MKRN3, showed altered methylation. IPA revealed enrichment in pathways related to leptin, sirtuin, estrogen, and GnRH signaling.

CONCLUSION

Young female adolescents with AN exhibited distinct methylation profiles, primarily hypomethylation, affecting genes involved in energy homeostasis and pubertal development. These epigenetic alterations may represent biomarkers of metabolic dysfunction and pubertal delay in AN.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40618-026-02830-6.