The role of common and rare genetic variation on adiposity across childhood

Our understanding of the genetic architecture of obesity has primarily been shaped by observations from adult populations with relatively few studies on childhood obesity. To address this gap, we conduct a longitudinal genetic association study in up to [~]600,000 individuals with objectively measured or recalled childhood adiposity-related traits. We identify 624 common variant signals (only 7% are previously reported) associated with childhood adiposity, of which one third have no concordant association with adult BMI. Signals linked to the leptin-melanocortin pathway (BSX, GNAS, LEPR and PCSK1) and incretin-signalling genes (GIPR and GLP1R) show stronger associations in childhood than in adults, suggesting that childhood provides a more sensitive window for detecting variation in key endocrine and neuropeptide pathways regulating energy balance. This observation is further supported by integrating single-nucleus RNA sequencing data from the human hypothalamus, identifying childhood-specific adiposity-regulating cell populations in the arcuate nucleus and mammillary bodies, indicating distinct neuro-circuits that regulate adiposity only during childhood. Three signals showed parent-of-origin specific associations with childhood BMI, at KLF14 (maternal-specific), GNAS (parental-discordant) and ZDBF2 (paternal-specific). Finally, we complement these common variant analyses with DNA sequence data in 479,615 individuals, identifying rare protein-coding variation in ADCY3, CALCR, MC4R, MRAP2, POMC and MYH13, all of which demonstrate stronger adiposity associations in childhood than in adults. Collectively, our findings emphasize the value of expanding research on childhood adiposity alongside studies focused on adult obesity measures.