Almost every paper on polygenic risk scores now reminds us that PRS should be adapted to ancestry. A new @NatureGenet study suggests another important dimension. Age. The authors studied BMI in 62,276 children across 11 age points from 6 weeks to 8 years. They identified 624 independent signals in the longitudinal analysis. Almost one third did not show the same effect in adults! For 165 signals the association disappeared and for 29 the effect reversed direction. A striking example is PCSK1. One variant increased BMI at around 8 months but was associated with lower BMI in adults. This fits its biology well because PCSK1 processes multiple hormones and neuropeptides and its role changes across development. The same pattern was seen with polygenic scores. At 8 to 12 months an age-matched genome-wide PGS explained 10.9% of BMI variance. A PGS trained on adult BMI explained only 1.3%. More than an eightfold difference. The underlying biology was familiar. The leptin melanocortin pathway was strongly enriched but different genes had different temporal profiles. LEPR and PCSK1 were more important early in life while MC4R POMC and BDNF showed more persistent effects. Signals were also found near GLP1R and GIPR. Some GLP1R variants acted mainly in early childhood. This is especially interesting because GLP1R is the receptor targeted by semaglutide in Ozempic. Similar results were seen for rare variants in nearly 480,000 genomes. The authors also found parent-of-origin effects. For example KLF14 acted mainly when the allele was inherited from the mother which fits its known imprinting. To me, this makes it clear that PRS may need to be adapted not only to ancestry but also to age. The difference can be dramatic. In infancy the right age-specific score explained more BMI variation than score trained in adults. The genome stays the same. Its effects do not. nature.com/articles/s41588-0… #GWAS #PRS #adiposity #BMI #snRNA