<i>HAGHL</i> genetic variants increase first fracture risk (FFR) in female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS) and St. Jude Lifetime Cohort Study (SJLIFE).
Bibliographic record
Abstract
10554 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. [Table: see text]
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".