The study’s scale is unprecedented for this age group. The team, led by researchers at the University of Cambridge and the University of Bergen, analysed age-standardised and sex-standardised BMI at eleven timepoints, from six weeks to eight years of age, in up to 62,276 children from the Norwegian Mother, Father and Child Cohort Study (MoBa). Across those timepoints they identified 369 genome-wide significant associations, which collapsed into 152 independent signals — a dramatic increase over the 25 loci found in the largest previous study of measured childhood BMI. Ninety-four percent of the 116 loci newly identified for BMI before age five had never been reported before, and none of the signals showed evidence of sex-specific effects.

A striking feature of the data is how much the genetic architecture of BMI changes with age. SNP-based heritability estimates rose after birth to a peak around the ‘adiposity peak’ at age one, then declined toward the ‘adiposity rebound’ around age five to six, mirroring the natural trajectory of body fat in early life. Genetic correlations told a similar story: the correlation between BMI in infancy and BMI in later childhood was only modest, at 0.39, and the correlation between childhood and adult BMI was lower still, at 0.19. In other words, the genetic variants that make a baby chubby are largely not the same ones that determine adult body size.

To push discovery further, the researchers used a statistical technique called genomic structural equation modelling to fuse three childhood-related traits into a single ‘childhood adiposity’ factor: BMI at age eight in MoBa, recalled comparative body size at age ten from 444,345 UK Biobank participants, and a genome-wide study of age at menarche, a trait tightly linked to early-life adiposity. This yielded an effective sample size of 599,924 individuals and 526 additional independent signals. A polygenic score built from the combined 624 signals explained up to 9.2 percent of variation in childhood BMI at age nine in the independent Avon Longitudinal Study of Parents and Children — outperforming scores based on adult BMI for every timepoint below age five.

When the team clustered the 624 signals by how their effects unfolded across childhood, two clear trajectories emerged. A ‘Transient’ group of 115 variants influenced BMI only during infancy, peaking between six weeks and about twelve months, while a ‘Persistent’ group of 507 variants continued to act into later childhood. The distinction matters clinically: in a disease-wide analysis of UK Biobank data, transient signals did not raise the risk of any adult disease and appeared mildly protective against type 2 diabetes and hypertension, whereas persistent signals raised cardiometabolic risk in ways that vanished once adult BMI was accounted for. The message is that infant fat that later resolves carries no long-term penalty — and may even confer benefit.

Gene-mapping analyses linked 434 high-confidence genes to the signals, and among them were eleven components of the leptin–melanocortin pathway, the master neuroendocrine circuit of appetite regulation whose disruption causes severe early-onset obesity. Signals tied to BSX, GNAS, LEPR and PCSK1 showed childhood-specific effects, while incretin pathway genes — GLP1R and GIPR, the very receptors targeted by today’s blockbuster weight-loss drugs — also emerged with effects confined largely to childhood. Notably, none of the GLP1R signals was associated with BMI beyond early childhood, and one PCSK1 variant even showed opposite effects on BMI in infancy and adulthood. Because the authors found that rare variants in these same pathways act more strongly in children than in adults, they suggest that drugs targeting the leptin–melanocortin pathway, such as leptin and setmelanotide, may be more effective in children than in adults.

Single-nucleus RNA sequencing data from the human hypothalamus added a neurobiological dimension. Childhood adiposity signals were enriched in 260 of 452 mapped hypothalamic cell populations, all of them neuronal — and nineteen of these were enriched only for childhood, not adult, signals. Five of the child-specific populations sit in the arcuate nucleus, the hypothalamic hub of energy homeostasis, and another five in the mammillary bodies, a region better known for memory. These cell populations were marked by expression of leptin–melanocortin and incretin components such as LEPR, POMC, MC4R, GLP1R and GIPR, hinting at brain circuits that regulate body fat specifically during development.

Whole-genome sequencing of 479,615 UK Biobank participants then extended the search to rare variants. Burden tests implicated six genes — ADCY3, CALCR, MC4R, MRAP2, POMC and MYH13 — with rare protein-coding variants that showed stronger associations with recalled childhood adiposity than with adult BMI. Four of the six encode central components of the leptin–melanocortin pathway, and the associations for ADCY3 and MRAP2 provided the first population-scale evidence that single copies of damaging variants in these severe-obesity genes measurably shift childhood body size. A novel association at MYH13, a muscle gene, affected childhood adiposity but showed no link to adult BMI at all.

The Norwegian cohort’s parent–child trios also allowed the team to probe genomic imprinting — the parent-of-origin silencing of certain genes. Evidence of imprinting emerged at signals near known imprinted regions, including a maternal effect at KLF14 on infancy BMI that reverses direction in adulthood, a childhood-specific paternal effect at GNAS, and a novel paternal-only association near ZDBF2, a gene that in mice regulates neonatal feeding and growth. The authors argue that these findings extend the classic parental-conflict hypothesis of imprinting, which was developed for fetal growth and puberty timing, to the regulation of childhood adiposity itself.

The study has limitations the authors acknowledge: the cohorts were of northern European ancestry, BMI in infancy is an imperfect proxy for fat mass, and the hypothalamic cell atlas was built from adult autopsy tissue. Larger, more diverse studies with directly measured infant body composition will be needed. Even so, the conclusion is hard to escape. With 624 signals — comparable to the 941 found for adult BMI in more than 700,000 people — childhood adiposity genetics proved at least as informative as its adult counterpart, and far more revealing about core energy-balance biology. As the authors put it, childhood appears to be a more sensitive window for detecting variation in the key endocrine and neuropeptide pathways that regulate how our bodies store fat, a finding that could reshape both obesity drug development and early-life prevention strategies.

Subject of Research: Genome-wide association and sequencing analysis of common and rare genetic variants influencing adiposity across childhood

Article Title: Genome-wide mapping of common and rare variant effects on adiposity across childhood

Article References: Kentistou, K. A., Sundfjord, J., Karimi, R., Kaisinger, L. R., Hofmeister, R. J., Fragoso-Bargas, N., Lupu, A. E., Zhao, Y., Tadross, J. A., Steuernagel, L., Dowsett, G. K. C., Lockhart, S., Brüning, J. C., Liu, J., Cortes, A., Lo, Y., Davitte, J., Clement, L., Havdahl, A., … Johansson, S. (2026). Genome-wide mapping of common and rare variant effects on adiposity across childhood. Nature Genetics. https://doi.org/10.1038/s41588-026-02772-y

Image Credits: AI Generated

DOI: 10.1038/s41588-026-02772-y

Keywords: childhood obesity, genome-wide association study, adiposity, leptin-melanocortin pathway, incretin signaling, hypothalamus, rare variants, genomic imprinting, polygenic scores, MoBa cohort, UK Biobank, BMI trajectories