Persistent Body Mass Index Profiles During Adolescence: Associations With Brain Maturation and DNA Methylation

Adolescence is a critical period for the emergence of obesity and disordered eating behaviors, 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 behavioral, neurodevelopmental, and epigenetic variation during adolescence.

Participants from the IMAGEN cohort (N = 1296) were followed from ages 14 to 23 years. Latent profile analysis identified longitudinal BMI profiles. Disordered eating behaviors were repeatedly assessed across adolescence. Structural magnetic resonance images acquired at ages 14 and 23 characterized longitudinal changes in gray matter volume (GMV), cortical thickness (CT), and sulcal depth. Genome-wide DNA methylation (DNAm) was measured in whole blood at age 14. We conducted epigenome-wide association studies (EWASs) and functional enrichment analyses and evaluated a DNAm-based BMI risk score (bmiMRS).

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 behaviors. They also exhibited atypical cortical maturation, characterized by attenuated cortical thinning, accelerated reductions in sulcal depth, and reduced gray 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 signaling, 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 CT predicted greater BMI increases independently of baseline BMI.

Persistent adolescent overweight is associated with distinct behavioral, neurodevelopmental, and peripheral epigenetic signatures. Integrating longitudinal neuroimaging and DNAm 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.