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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.
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
URL: https://doi.org/10.1093/hmg/ddac251
DOI: 10.1093/hmg/ddac251
ePrints DOI: 10.57711/zyq4-8j98
PubMed id: 36209419
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