부산대학교 도서관

Background:Several small genetic association studies have been conducted for atypical femurfracture (AFF) without replication of results. We assessed previously implicated and novel genesassociated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES).Methods:We performed gene-based association analysis on 139 European AFF cases and 196 controlsmatched for bisphosphonate use. We tested all rare, protein-altering variants using both candidategene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs(uncorrected p-values < 0.01) were investigated in a Swedish whole-genome sequencing replicationstudy and assessed in 46 non-European cases.Results:In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-freeapproach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likelycandidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in thereplication analysis, albeit not statistically significant. Three SNPs associated with SORD expressionaccording to the GTEx portal, were in linkage disequilibrium (R2 ≥0.2) with a SNP previouslyreported in a genome-wide association study of AFF. The prevalence of carriers of variants for bothPLOD2 and SORD was higher in Asian versus European cases.Conclusions:While we did not identify genes enriched for damaging variants, we found suggestiveevidence of a role for XRN2, PLOD2 and SORD, which requires further investigation. Our findingsindicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The studyprovides a stepping-stone for future larger genetic studies of AFF.