Genome-wide study of the UK Biobank highlights the importance of the homeobox-C gene cluster in hip fracture risk
Author(s)
Koizia, Louis
Giovannantonio, Matteo Di
Zhang, Ping
Fertleman, Michael Barry
Harris, Benjamin Howell Lole
Type
Journal Article
Abstract
Introduction
Hip fractures are among the most common major orthopaedic injuries globally, with one in three women and one in twelve men projected to sustain a hip fracture in their lifetime. Identifying genetic factors that contribute to hip fracture risk could improve risk stratification and inform prevention strategies. This study aims to identify genetic variants associated with hip fracture susceptibility through a genome-wide association study (GWAS).
Materials and Methods
A GWAS was undertaken using the UK Biobank to identify risk loci for hip fractures.
Results
At the time of analysis, 2165 neck of femur fractures were identified among the 502 507 participants. Thirteen SNPs in five putative haplotypes were identified as significantly associated with hip fracture using the stringent GWAS threshold of 5E-8. Two of these loci appear to affect HOXC8, either by influencing the 3’ UTR (rs4142680[T]) or via the miRNA hsa-miR-196a (rs11614913[T]). These two SNPs were also found to be expression quantitative trait loci for homeobox-C cluster genes (HOXC6, HOXC9, and HOXC-AS1).
Conclusions
Polymorphisms affecting homeobox-C cluster genes influence hip fracture risk in the general population. Future research should focus on validating these genetic associations and exploring optimal therapeutic interventions that could mitigate fracture risk in subpopulations carrying these polymorphisms.
Hip fractures are among the most common major orthopaedic injuries globally, with one in three women and one in twelve men projected to sustain a hip fracture in their lifetime. Identifying genetic factors that contribute to hip fracture risk could improve risk stratification and inform prevention strategies. This study aims to identify genetic variants associated with hip fracture susceptibility through a genome-wide association study (GWAS).
Materials and Methods
A GWAS was undertaken using the UK Biobank to identify risk loci for hip fractures.
Results
At the time of analysis, 2165 neck of femur fractures were identified among the 502 507 participants. Thirteen SNPs in five putative haplotypes were identified as significantly associated with hip fracture using the stringent GWAS threshold of 5E-8. Two of these loci appear to affect HOXC8, either by influencing the 3’ UTR (rs4142680[T]) or via the miRNA hsa-miR-196a (rs11614913[T]). These two SNPs were also found to be expression quantitative trait loci for homeobox-C cluster genes (HOXC6, HOXC9, and HOXC-AS1).
Conclusions
Polymorphisms affecting homeobox-C cluster genes influence hip fracture risk in the general population. Future research should focus on validating these genetic associations and exploring optimal therapeutic interventions that could mitigate fracture risk in subpopulations carrying these polymorphisms.
Date Issued
2025-05-01
Date Acceptance
2025-04-02
Citation
Geriatric Orthopaedic Surgery & Rehabilitation, 2025, 16
ISSN
2151-4593
Publisher
SAGE Publishing
Journal / Book Title
Geriatric Orthopaedic Surgery & Rehabilitation
Volume
16
Copyright Statement
© The Author(s) 2025. This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
License URL
Identifier
10.1177/21514593251336568
Subjects
UK Biobank
GWAS
hip fracture
HOX-C gene cluster
HOXC6
HOXC8
HOXC9
HOXC-AS1
rs4142680
rs11614913
neck of femur
Publication Status
Published
Article Number
21514593251336568
Date Publish Online
2025-04-16