Background:Previous studies have demonstrated the influence of heritable factors on the development of nontraumatic osteonecrosis of the femoral head (ONFH). We hypothesized that genetic variation is associated with an increased risk of ONFH, and that variants could be identified by a genomewide association study (GWAS).Methods:Using data collected from the MyCode Community Health Initiative, we identified 118 adult patients with radiographically confirmed nontraumatic ONFH. Study patients were statistically compared with a control population of 56,811 unrelated individuals without a diagnosis of ONFH. A case-control GWAS was performed to identify single nucleotide variants (SNVs) associated with ONFH. Sensitivity analyses were performed to evaluate the association of the top SNVs with (cortico)steroid-associated ONFH and ONFH with femoral head collapse. Gene-based analyses were performed to identify potential causal genes.Results:Of the 118 patients, 114 (96.6%) had bilateral ONFH at a median of 5 years of follow-up; 90.7% had at least one 3-week steroid prescription compared with 68.3% in controls. A GWAS identified 4 SNVs reaching genomewide significance. rs116468452 nearCACNA1Ewas significantly associated with ONFH (p = 3.26 × 10−9, odds ratio [OR] = 5.6, 95% confidence interval [CI] = 3.21 to 9.76). rs10953090 inSAMD9was significantly associated with ONFH in the steroid-exposed subset (p = 2.96 × 10−8, OR = 2.57, 95% CI = 1.84 to 3.58). rs112467115 inPI4K1Bshowed enhanced association in the collapsed subset (p = 7.82 × 10−8, OR = 4.5, 95% CI = 2.60 to 7.79). Gene-based analyses identifiedPPARGC1Bas the only gene significantly associated with ONFH after Bonferroni correction (p = 1 × 10−6), with the lead SNV being rs78814834 (OR = 2.86, 95% CI = 1.87 to 4.38).Conclusions:We identified 4 SNVs and 1 gene,PPARGC1B,associated with ONFH.Level of Evidence:PrognosticLevel IV. See Instructions for Authors for a complete description of levels of evidence.