This study aimed to identify genetic variants associated with Lp(a) lipoprotein levels and coronary disease. Using a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes, the researchers tested for associations in 3145 case subjects with coronary disease and 3352 control subjects. Three chromosomal regions (6q26–27, 9p21, and 1p13) were strongly associated with coronary disease risk. The LPA locus on 6q26–27 showed the strongest association, with two common variants (rs10455872 and rs3798220) explaining 36% of the variation in Lp(a) lipoprotein levels. These variants were independently associated with an increased risk of coronary disease, and their effects correlated with Lp(a) lipoprotein levels. Replication studies in three independent populations confirmed these associations. After adjusting for Lp(a) lipoprotein levels, the association between the LPA genotype score and coronary disease risk was abolished. The findings provide strong evidence for a causal role of elevated Lp(a) lipoprotein levels in coronary disease.This study aimed to identify genetic variants associated with Lp(a) lipoprotein levels and coronary disease. Using a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes, the researchers tested for associations in 3145 case subjects with coronary disease and 3352 control subjects. Three chromosomal regions (6q26–27, 9p21, and 1p13) were strongly associated with coronary disease risk. The LPA locus on 6q26–27 showed the strongest association, with two common variants (rs10455872 and rs3798220) explaining 36% of the variation in Lp(a) lipoprotein levels. These variants were independently associated with an increased risk of coronary disease, and their effects correlated with Lp(a) lipoprotein levels. Replication studies in three independent populations confirmed these associations. After adjusting for Lp(a) lipoprotein levels, the association between the LPA genotype score and coronary disease risk was abolished. The findings provide strong evidence for a causal role of elevated Lp(a) lipoprotein levels in coronary disease.