Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.Coronary artery disease (CAD) due to atherosclerosis results in myocardial infarction (MI) and is the leading cause of death worldwide (1). Epidemiologic studies and clinical intervention trials have established the key roles of specific risk factors for CAD, including smoking, hypertension, high low-density lipoprotein (LDL) cholesterol, high triglycerides, low highdensity lipoprotein (HDL) cholesterol, and diabetes mellitus (2-4). Surprisingly, many of these risk factors cluster with one another more often than expected by chance (5,6). This metabolic syndrome is recognized to be a common cause of CAD; however, the molecular mechanisms that unify their association have been obscure.The marked increase in risk of early cardiovascular mortality to a second monozygotic twin when the first has died from early CAD provides evidence for a strong genetic effect and supports investigation of families with early disease (7). Such studies have the capacity to