Introduction: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with HMG-CoA reductase inhibitors (statins) decreases circulating levels of low-density lipoprotein cholesterol (LDL-C) and the incidence of CHD, additional events occur despite statin therapy in some individuals. In this study, we aimed to identify genetic variants associated with CHD events occurring during statin therapy.Methods: The main outcomes of this study are CHD events during statin therapy. We performed a two-stage genome-wide association study (GWAS). We first identified 3,099 cases who experienced CHD events (myocardial infarction or coronary revascularization) during statin therapy and 7,681 controls without CHD events during comparable intensity and duration of statin therapy from four sites in the Electronic Medical Records and Genomics (eMERGE) Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth eMERGE site, which joined the network after the initial GWAS.Results: The first-stage meta-analysis identified seven SNPs at a genome-wide level of significance within the LPA/PLG locus and one SNP within TGM6 associated with CHD events on statin treatment. The most significant association was for an intronic SNP within LPA/PLG (rs10455872, MAF=0.069, Odds Ratio [OR]=1.58, 95% CI [1.35-1.86], P=2.6х10–10). In the replication cohort, rs10455872 was associated with CHD events (OR=1.85, p=0.0057). The association of this SNP with CHD events was independent of statin-induced change in LDL-C (Odds Ratio=1.62, 95% CI [1.17-2.24]).Conclusions: A GWAS approach identified variants at the LPA locus to be associated with CHD events during statin therapy, independent of the extent of LDL-C lowering. This finding provides support for clinical trials to assess whether drugs that lower lipoprotein (a) levels reduce CHD events in patients on statins.