Katherine A Kentistou, Jonas Sundfjord, Roya Karimi, Lena R Kaisinger, Robin J Hofmeister, Nicolas Fragoso-Bargas, Adina E Lupu, Yajie Zhao, John A Tadross, Lukas Steuernagel, Georgina K C Dowsett, Sam Lockhart, Jens C Brüning, Jimmy Liu, Adrian Cortes, Yancy Lo, Jonathan Davitte, Lieven Clement, Alexandra Havdahl, Ole A Andreassen, Eirik Bratland, Brian Y H Lam, Stephen O'Rahilly, Giles S H Yeo, Pål R Njølstad, Zoltán Kutalik, Felix R Day, Marc Vaudel, John R B Perry, Ken K Ong, Stefan Johansson
Our understanding of the genetic architecture of obesity is primarily based on studies of adults, with sparser data from childhood. Here, we conducted age-stratified genetic association studies against objectively measured (n = 62,276) or recalled childhood adiposity-related traits (neff = 599,924), identifying 624 common variants associated with childhood adiposity, with one-third having no concordant association with adult body mass index. Signals linked to the leptin-melanocortin pathway (BSX, GNAS, LEPR and PCSK1) and incretin signaling (GIPR and GLP1R) showed childhood-specific effects on adiposity. Single-nucleus RNA sequencing data identified childhood-specific adiposity-regulating cell populations in the arcuate nucleus and mammillary bodies, indicating neurocircuits that regulate adiposity specifically during childhood. Finally, sequencing in 479,615 individuals uncovered rare protein-coding variation in ADCY3, CALCR, MC4R, MRAP2, POMC and MYH13, exhibiting stronger associations in childhood than in adults. Our findings suggest that childhood provides a more sensitive window for the study of key endocrine and neuropeptide pathways that regulate energy balance.