Therapy related osteonecrosis has become a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL). Prior studies on the genetic determinants of osteonecrosis have focused on patients 10 years and older, leaving the genetic risk factors for the larger group of children younger than 10 years incompletely understood. Here, we perform the first evaluation of genetic risk factors for osteonecrosis in children less than 10 years old. The discovery cohort comprised 82 cases of osteonecrosis and 287 controls treated on Children's Oncology Group (COG) standard-risk ALL protocol AALL0331 (NCT00103285, https://clinicaltrials.gov/ct2/show/NCT00103285), with results tested for replication in 817 children less than 10 years treated on COG high-risk ALL protocol AALL0232 (NCT00075725, https://clinicaltrials.gov/ct2/show/NCT00075725). The top replicated SNPs were located near bone morphogenic protein 7 [BMP7: rs79085477 and rs75161997, P=5.34x10-8 (OR 15.0) and P=0.0498 (OR 8.44) in the discovery and replication cohorts, respectively] and PROX1-antisense RNA1 [PROX1-AS1: rs1891059, P=2.28x10-7 (OR 6.48) and P=0.0077 (OR 3.78) for the discovery and replication cohorts, respectively]. The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene [GRID2, P=8.65x10-6 (OR 3.46) and P=0.0136 (OR 10.8) in the discovery and replication cohorts, respectively]. In a meta-analysis, the replicated BMP7 and PROX1-AS1 variants (rs75161997 and rs1891059, respectively) met the genome-wide significance threshold of <5x10-8. Top replicated SNPs were enriched in enhancers active in mesenchymal stem cells, and pathway analysis of annotated genes demonstrated enrichment in glutamate receptor signaling and adipogenesis pathways. These data may provide new insights into the pathophysiology of osteonecrosis.