FROM MONOGENIC SYNDROMES TO POLYGENIC RISK AND EPIGENETIC PROGRAMMING: THE GENETIC ARCHITECTURE OF CHILDHOOD OBESITY AND ITS IMPLICATIONS FOR PERSONALIZED THERAPY

Abstract

Childhood obesity is a heritable trait, with twin studies estimating BMI heritability at 40–70%, yet loci identified through genome-wide association studies still explain only a fraction of this variance. This review synthesizes evidence on the genetic architecture of pediatric obesity across three mechanistic tiers. First, monogenic forms arising from mutations in the leptin–melanocortin pathway (LEP, LEPR, POMC, PCSK1, MC4R) produce early, intense hyperphagia and severe obesity amenable to targeted pharmacotherapy, including metreleptin and the melanocortin-4 receptor agonist setmelanotide. Second, the polygenic architecture uncovered by genome-wide association studies now spans more than one hundred loci, including FTO, MC4R, and ADCY3, distilled into polygenic risk scores that, drawing on data from over five million individuals across ancestries, explain up to 17.6% of BMI variance in European-ancestry adults and predict accelerated weight gain from as early as 2.5 years of age in the ALSPAC cohort. Third, epigenetic programming in utero, evidenced most clearly by cord-blood methylation studies from the Boston Birth Cohort, links maternal adiposity and inflammation to offspring obesity risk through specific CpG sites, with mediated proportions of the maternal-to-child obesity association reaching 25%. We integrate longitudinal cohort data from ALSPAC and the Boston Birth Cohort to quantify how these tiers jointly shape weight trajectories from infancy through adolescence, and discuss pharmacogenetic predictors of treatment response. We conclude that genetic evaluation is becoming a practical instrument for early risk stratification and mechanism-based treatment selection in pediatric obesity, provided polygenic tools are validated and re-derived across ancestries.