Gene-based association analysis of a large patient cohort provides insights into genetics of atypical femur fractures
Authors' conclusion
While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2, and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases.
Study context
- Population
- Unrelated European patients with atypical femur fracture (AFF) and bisphosphonate-use-matched controls; 46 non-European cases also assessed
- Participants
- 139 vs 196
- Comparison
- European AFF cases vs controls matched for bisphosphonate use
- AFF casesn = 139
- Controlsn = 196reference
- Outcome
- Gene-based association of rare, protein-altering variants with AFF
Methodological detailswhole exome sequencing, gene-based association analysis, candidate gene and hypothesis-free approaches, controls matched for bisphosphonate use, Swedish whole-genome sequencing replication study
- Whole exome sequencing
- Gene-based association analysis
- Candidate gene and hypothesis-free approaches
- Controls matched for bisphosphonate use
- Swedish whole-genome sequencing replication study
Main finding
As reported in the abstract
Gene-based association with AFF
- Hypothesis-free approach: tentative associations
- 10
Observational data: associations, not effects.
Further findings
Replication (Swedish whole-genome sequencing study)
- XRN2 and PLOD2 showed consistent direction of effect estimates, not statistically significant
SORD expression SNPs (GTEx)
- SNPs associated with SORD expression in linkage disequilibrium (R2 ≥ 0.2) with an SNP previously reported in a GWAS of AFF
- 3
Carriers of PLOD2 and SORD variants by ancestry
- Prevalence of carriers of variants for both PLOD2 and SORD higher in Asian vs European cases
- 46 non-European cases
Original publication
Gene-based association analysis of a large patient cohort provides insights into genetics of atypical femur fractures. J Bone Miner Res. Published 10 August 2024. doi:10.
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