Objectives—Identify gene variants associated with early-onset myocardial infarction (MI).Methods and Results—We tested 11 647 single-nucleotide polymorphisms (SNPs) for association with early-onset MI in a case-control study (study 1 200 cases, 262 controls). To reduce the number of false positives among the 666 SNPs that were nominally associated with early-onset MI (P<0.05) in study 1, we tested these SNPs in study 2 (434 cases, 504 controls). We found that 8 of the 666 SNPs were associated with early-onset MI in study 2 (P<0.05) and had the same risk alleles as in study 1. These 8 SNPs were then tested for association with early-onset MI in study 3 (187 cases, 434 controls). We found that a VAMP8 variant (P=0.025; odds ratio [OR], 1.75; CI, 1.17 to 2.62) and an HNRPUL1 variant (P=0.0043; OR, 1.92; CI, 1.28 to 2.86) were associated with early-onset MI (nominalP<0.05; false discovery rate <10%) and had the same risk alleles in all 3 studies.Conclusions—Variants in 2 genes were associated with early-onset MI: VAMP8, which is involved in platelet degranulation, and HNRPUL1, which encodes a ribonuclear protein. The identification of these variants could improve understanding of disease mechanisms and suggest novel drug targets.