Genetic risk of osteoarthritis operates during human skeletogenesis

Abstract

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.

Mediation of the Same Epigenetic and Transcriptional Effect by Independent Osteoarthritis Risk–Conferring Alleles on a Shared Target Gene, COLGALT2

“…Identification of OA genetic risk mechanisms at the rs1046934 locus in human fetal development. As noted earlier, we recently reported that, for several OA SNPs, the associations between gene expression and CpG methylation observed in human arthroplasty cartilage also occur in fetal cartilage (24). Therefore, we determined whether the rs1046934 AEI, mQTL, and meQTL effects were also detectable in fetal cartilage.…”

“…This implies that a proportion of OA genetic risk is functionally active during skeletogenesis and early post-natal life and manifests with ageing (44)(45)(46). We previously investigated this by assessing AEI and mQTLs at OA risk loci in foetal cartilage samples (24).…”

“…For a proportion of the studied loci, the AEI and mQTLs observed in arthroplasty cartilage were also observed in fetal cartilage (24). This included the rs11583641 COLGALT2 locus (24), which prompted us to investigate fetal cartilage at the rs1046934 locus. The rs1046934 AEI, mQTL, and meQTL effects detected in human arthroplasty cartilage were also detected in fetal cartilage, implying that this locus is one in which the molecular effects on a target gene are activated during development.…”

“…As noted earlier, we recently reported that for several OA SNPs the associations with gene expression and CpG methylation observed in arthroplasty cartilage 23265205, ja, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/art.42427 by NEWCASTLE UNIVERSITY, Wiley Online Library on [22/12/2022]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License also occur in foetal cartilage (24). We therefore determined whether the rs1046934 AEI, mQTL and meQTL effects were also detectable in foetal cartilage.…”

“…See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License concluded that increased COLGALT2 expression, and therefore increased galactosyltransferase activity, could be detrimental to cartilage health via impacts on collagen biosynthesis (22). We subsequently reported that for some OA risk loci, including rs11583641, genotype associations with gene expression and CpG methylation observed in arthroplasty cartilage are also observed in foetal cartilage (24). This implies that OA genetic risk may be programmed in during development.…”