A selected distal enhancer orchestrates avian fat deposition in coordination with ADM signaling

Fat deposition represents a global health threat, yet its underlying genetic architecture remains unresolved. While genome-wide association studies (GWAS) have identified thousands of risk loci, the vast majority reside within noncoding regions—functional “dark matter” whose regulatory roles are difficult to decipher. To overcome these challenges, we utilize the duck as a unique metabolic model; its extreme lipogenic efficiency provides a powerful biological lens through which the regulatory mechanisms of noncoding variants can be effectively unmasked. In this study, we decoded the regulatory architecture of duck adiposity by integrating epigenomic, 3D genomic, and transcriptomic landscapes across two divergent duck lines. By developing a “mixed-strategy” gene prioritization, combining weighted gene co-expression network analysis (WGCNA) with a Bayesian framework, we successfully narrowed down gene regulators to 112 high-confidence candidate genes. Notably, we unmasked a master regulatory switch: a key selected SNP that remotely modulates ADM expression specifically through recruiting the transcription factor SMAD2 . Relevant evidences indicate that ADM acts as a cellular signal, driving fat deposition through promoting cell proliferation and differentiation in subcutaneous adipose tissue. These findings reveal that a selected distal enhancer drives ADM expression to promote subcutaneous fat deposition by enhancing preadipocyte proliferation and differentiation. Beyond illuminating the regulatory logic of avian adiposity, this study provides a high-resolution epigenomic map and a precision blueprint for genetic selection in ducks.