Scalable Deep Learning of Histology Images Reveals Genetic and Phenotypic Determinants of Adipocyte Hypertrophy.

Background: White adipose tissue dysfunction has emerged as a critical factor in cardiometabolic disease development, yet the cellular microstructure and genetic architecture of adipocyte morphology remain poorly explored.

Methods: We introduce Adipocyte U-Net 2.0, an advanced deep learning method for the semantic segmentation of adipose tissue histology, enabling analysis of over 27 million adipocytes from 2,667 individuals.

Findings: Our approach revealed that adipocyte hypertrophy associates with metabolic dysfunction, including increased fasting glucose, glycated hemoglobin, leptin, and triglycerides, with decreased adiponectin and HDL cholesterol levels. Through the largest genome-wide association study of adipocyte size to date (N _Subcutaneous = 2,066, N _Visceral = 1,878), we identified four genome-wide significant loci: two in sex-combined analysis (rs73184721 in NAALADL2 and rs200047724 in NRXN3 ) and two female-specific variants (rs140503338 and rs11656704 in ULK2 ). Notably, these genetic associations showed congruent relationships with cardiometabolic traits, suggesting shared biological mechanisms.

Interpretation: Our findings demonstrate the utility of deep learning for adipocyte phenotyping at scale and provide novel insights into the genetic basis of adipocyte morphology and its relationship to metabolic disease.