Abstract
Modern lifestyles often disturb circadian rhythms, yet the genetic circuits that convert this stress into metabolic dysfunction remain poorly defined. Here, we identify a missense variant in ADCY3 (rs11676272; Ser107Pro) as a pleiotropic regulator of circadian preference and adiposity. Using genome-wide pleiotropy analysis in ∼480,000 UK Biobank participants, we show that the G risk allele (Pro107) increases eveningness, BMI, and fat mass in European (n = 451,324) and African (n = 8,738) ancestry groups, with behavioral amplification by morning difficulty awakening in Europeans and power-limited modeling in other populations. Structural modeling and transcriptomic analysis suggest this allele alters adipose-specific splicing and expression and destabilizes ADCY3 protein. In mice, Adcy3 is rhythmically expressed in adipose tissue, with BMAL1 binding near the orthologous residue 107 site. Human adipose ADCY3 expression also increases after weight loss. Together, these findings reveal a genotype-dependent, behaviorally modifiable axis connecting difficulty awakening to metabolic risk through circadian and adipose regulatory pathways.