Human Genetics of Adipose Dysfunction: Genomic Mechanisms and Therapeutic Opportunities in Cardiometabolic Disease

Cardiometabolic diseases are a leading cause of global morbidity and mortality and arise from shared and distinct risk factors acting through interconnected biological pathways. Although excess adiposity is a major risk factor, body mass index incompletely captures cardiometabolic risk, reflecting heterogeneity in overall and regional fat storage capacity and ectopic lipid accumulation. Failure of subcutaneous adipose tissue to expand appropriately promotes lipid overflow into visceral and ectopic depots, contributing to insulin resistance, dyslipidemia, and organ dysfunction. Human genetic studies have identified thousands of genetic loci influencing fat storage, fat distribution, and ectopic lipid accumulation, revealing that these traits reflect distinct underlying mechanisms with divergent cardiometabolic consequences. Recent scaling of genetic discovery for refined adiposity and cardiometabolic phenotypes and multitrait genetic approaches have advanced understanding of adipose-driven disease heterogeneity. We highlight variant-to-function strategies to resolve causal pathways and discuss emerging scalable approaches to accelerate biological learning from genetic discovery and translate these insights into adipose-directed therapeutics for cardiometabolic disease.