Toggle Main Menu Toggle Search

Open Access padlockePrints

Genetic risk of osteoarthritis operates during human skeletogenesis

Lookup NU author(s): Dr Sarah RiceORCiD, Abby Brumwell, Julia Falk, Yulia Kehayova, John CasementORCiD, Dr Eleanor Parker, Ines Hofer, Dr Colin Shepherd, Professor John LoughlinORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Osteoarthritis (OA) is a polygenic disease of older people resulting in the breakdown of cartilage within articular joints. Although a leading cause of disability, there are no disease-modifying therapies. Evidence is emerging to support the origins of OA in skeletogenesis. Whilst methylation QTLs (mQTLs) co-localizing with OA GWAS signals have been identified in aged human cartilage and used to identify effector genes and variants, such analyses have never been conducted during human development. Here, for the first time, we have investigated the developmental origins of OA genetic risk at seven well-characterized OA risk loci, comprising 39 OA-mQTL CpGs, in human foetal limb (FL) and cartilage (FC) tissues using a range of molecular genetic techniques. We compared our results to aged cartilage samples (AC) and identified significant OA-mQTLs at 14 CpGs and 29 CpGs in FL and FC tissues, respectively. Differential methylation was observed at 26 sites between foetal and aged cartilage, with the majority becoming actively hypermethylated in old age. Notably, 6/9 OA effector genes showed allelic expression imbalances during foetal development. Finally, we conducted ATAC-sequencing in cartilage from the developing and aged hip and knee to identify accessible chromatin regions, and found enrichment for transcription factor binding motifs including SOX9 and FOS/JUN. For the first time, we have demonstrated the activity of OA-mQTLs and expression imbalance of OA effector genes during skeletogenesis. We show striking differences in the spatiotemporal function of these loci, contributing to our understanding of OA aetiology, with implications for the timing and strategy of pharmacological interventions.

Publication metadata

Author(s): Rice SJ, Brumwell A, Falk J, Kehayova YS, Casement J, Parker E, Hofer IMJ, Shepherd C, Loughlin J

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2023

Volume: 32

Issue: 13

Pages: 2124-2138

Print publication date: 01/07/2023

Online publication date: 09/10/2022

Acceptance date: 04/10/2022

Date deposited: 10/10/2022

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddac251

ePrints DOI: 10.57711/zyq4-8j98

PubMed id: 36209419


Altmetrics provided by Altmetric


Funder referenceFunder name
20771VERSUS Arthritis (formerly Arthritis Research UK)