Persistent BMI profiles during adolescence: Associations with brain maturation and DNA methylation

Background Adolescence is a critical period for the emergence of obesity and disordered eating behaviours, yet the biological mechanisms underlying persistent differences in body mass index (BMI) development remain poorly understood. We investigated whether longitudinal BMI profiles are associated with behavioural, neurodevelopmental, and epigenetic variation during adolescence. Methods Participants from the IMAGEN cohort ( N = 1,296) were followed from ages 14 to 23 years. Latent profile analysis identified longitudinal BMI profiles. Disordered eating behaviours were repeatedly assessed across adolescence. Structural MRI acquired at ages 14 and 23 characterised longitudinal changes in grey matter volume (GMV), cortical thickness (CT), and sulcal depth (SD). Genome-wide DNA methylation was measured in whole blood at age 14. Epigenome-wide association studies (EWAS), functional enrichment analyses, and a DNA methylation-based BMI risk score (bmiMRS) were conducted. Results Two distinct BMI profiles were identified: a persistently overweight group and a persistently normal-weight group. Adolescents with persistent overweight showed progressively increasing BMI, greater eating-, weight-, and shape-related concerns, and more frequent dieting and binge-eating behaviours. They also exhibited atypical cortical maturation, characterised by attenuated cortical thinning, accelerated reductions in sulcal depth, and reduced grey matter volume loss within frontal and temporal association cortices. EWAS identified 29 BMI-associated CpGs (Bonferroni-corrected P < 1.3×10 -7 ), enriched for genes involved in adipogenesis, immune and inflammatory signalling, type 2 diabetes, and brain-related biological processes. The bmiMRS predicted BMI, cumulative BMI across adolescence, and membership of the persistently overweight group, and remained significantly associated with BMI in an independent cohort. Longitudinal analyses further suggested reciprocal associations between BMI and brain maturation, with higher BMI in early adolescence predicting subsequent regional GMV changes, whereas lower baseline cortical thickness predicted greater BMI increases independently of baseline BMI. Conclusions Persistent adolescent overweight is associated with distinct behavioural, neurodevelopmental, and peripheral epigenetic signatures. Integrating longitudinal neuroimaging and DNA methylation identifies molecular biomarkers and brain developmental features associated with sustained BMI elevation, providing a framework for earlier risk stratification and informing biologically grounded approaches to obesity prevention.