This study develops an alternative approach to traditional forward genetics for identifying gene networks that are perturbed by susceptibility loci and contribute to complex diseases. By integrating co-expression networks and genotypic data from a segregating mouse population, the authors identify a macrophage-enriched sub-network in liver and adipose tissues that is associated with metabolic traits such as obesity, diabetes, and atherosclerosis. This sub-network, referred to as the Macrophage-Enriched Metabolic Network (MEMN), is enriched for genes with causal relationships with these metabolic traits. Three genes—lipoprotein lipase (Lpl), lactamase β (Lactb), and protein phosphatase 1-like (Ppm1l)—are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. The study demonstrates that complex traits like obesity are emergent properties of molecular networks modulated by genetic loci and environmental factors, providing a more comprehensive view of the genetic and molecular basis of disease.This study develops an alternative approach to traditional forward genetics for identifying gene networks that are perturbed by susceptibility loci and contribute to complex diseases. By integrating co-expression networks and genotypic data from a segregating mouse population, the authors identify a macrophage-enriched sub-network in liver and adipose tissues that is associated with metabolic traits such as obesity, diabetes, and atherosclerosis. This sub-network, referred to as the Macrophage-Enriched Metabolic Network (MEMN), is enriched for genes with causal relationships with these metabolic traits. Three genes—lipoprotein lipase (Lpl), lactamase β (Lactb), and protein phosphatase 1-like (Ppm1l)—are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. The study demonstrates that complex traits like obesity are emergent properties of molecular networks modulated by genetic loci and environmental factors, providing a more comprehensive view of the genetic and molecular basis of disease.