Background: Recent genome-wide association studies (GWAS) have reported substantial sex differences in the genetic architectures of bone-related phenotypes. We investigated sex-specific genetic determinants of FFR in survivors of childhood cancer. Methods: We performed sex-combined and sex-stratified GWAS for FFR using Cox regression models fitted on follow-up age in 2,453 long-term (≥5 years) survivors in CCSS with ~5.4 million imputed SNPs (minor allele frequency, MAF≥5%), with self-reported FFR defined by first fracture at any site after diagnosis. Replication analyses were conducted in an independent sample of 1,417 SJLIFE survivors with whole-genome sequencing and clinician-assessed FFR. All models were adjusted for relevant genetic (e.g., ancestry) and clinical (e.g., height, weight, treatment) factors. Results: Sex-combined and male-specific analyses yielded no associations with P < 10^−7. Among female CCSS survivors (N = 1,289, 33% ≥1 fractures), we discovered 7 genome-wide significant (P < 5x10⁻⁸) SNP-FFR associations with strong evidence of sex effect heterogeneity (P < 7x10⁻⁶) across 2 independent loci with no known associations with bone phenotypes. We replicated these associations in SJLIFE (P≤0.05) for 3 coding SNPs in the HAGHL gene (16p13.3), among which rs1406815 showed the strongest association (MAF = 20%, meta-analysis HR = 1.43, P = 8.2x10⁻⁹; N = 1,935 women, 35% ≥1 fractures). We observed increased HAGHL SNP effects on FFR that corresponded with increasing head/neck (HN) radiation therapy (RT) dose (Table). Public omics data show replicated SNPs are associated with differential HAGHL expression in sex gland and musculoskeletal tissues (GTEx) and in osteoblasts treated with dexamethasone or prostaglandins (GRASP), suggesting sex-/therapy-specific biological pathways involving HAGHL SNPs for fracture are plausible. Conclusions: Novel associations between HAGHL genetic variants and FFR potentially reveal new sex- and therapy-specific biological mechanisms underlying bone-related health conditions in survivors of childhood cancer.

U.S. National Institutes of Health