© 2015 American Heart Association, Inc. RATIONALE:: Coronary Artery Disease (CAD) is a critical determinant of morbidity and mortality. Previous studies have identified several cardiovascular disease (CVD) risk factors, which may partly arise from a shared genetic basis with CAD, and thus be useful for discovery of CAD genes. OBJECTIVE:: We aimed to improve discovery of CAD genes, and inform the etiologic relationship between CAD and several CVD risk factors using a shared polygenic signal-informed statistical framework. METHODS AND RESULTS:: Using genome-wide association studies (GWAS) summary statistics and shared polygenic pleiotropy-informed conditional and conjunctional false discovery rate (FDR) methodology, we systematically investigated genetic overlap between CAD and 8 traits related to CVD risk factors: low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides (TG), type 2 diabetes (T2D), C-reactive protein (CRP), body mass index (BMI), systolic blood pressure (SBP) and type 1 diabetes (T1D). We found significant enrichment of single nucleotide polymorphisms (SNPs) associated with CAD as a function of their association with LDL, HDL, TG, T2D, CRP, BMI, SBP and T1D. Applying the conditional FDR method to the enriched phenotypes, we identified 67 novel loci associated with CAD (overall conditional FDR < 0.01). Further, we identified 53 loci with significant effects in both CAD and at least one of LDL, HDL, TG, T2D, CRP, SBP and T1D. CONCLUSIONS:: The observed polygenic overlap between CAD and cardio-metabolic risk factors indicates an etiological relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to CAD.