Traditional genome-wide scans for positive selection have mainly uncovered selective sweeps associated with monogenic traits. While selection on quantitative traits is much more common, very few signals have been detected because of their polygenic nature. We searched for positive selection signals underlying coronary artery disease (CAD) in worldwide populations, using novel approaches to quantify relationships between polygenic selection signals and CAD genetic risk. We identified candidate adaptive loci that may have been directly modified by disease pressures given their significant associations with CAD genetic risk. Top candidates were consistently associated with reproductive-traits suggesting antagonistic-pleiotropic tradeoffs with early-life phenotypes and also showed more evidence of gene regulatory effects in HapMap3 lymphoblastoid cell lines than non-adaptive candidates. Our study provides a novel approach for detecting selection on polygenic traits and evidence that modern human genomes have evolved in response to CAD-induced selection pressures and other early-life traits sharing pleiotropic links with CAD.