Interplay between genetics and epigenetics in osteoarthritis


Research into the molecular genetics of osteoarthritis (OA) has been substantially bolstered in the past few years by the implementation of powerful genome-wide scans that have revealed a large number of novel risk loci associated with the disease. This refreshing wave of discovery has occurred concurrently with epigenetic studies of joint tissues that have examined DNA methylation, histone modifications and regulatory RNAs. These epigenetic analyses have involved investigations of joint development, homeostasis and disease and have used both human samples and animal models. What has become apparent from a comparison of these two complementary approaches is that many OA genetic risk signals interact with, map to or correlate with epigenetic mediators. This discovery implies that epigenetic mechanisms, and their effect on gene expression, are a major conduit through which OA genetic risk polymorphisms exert their functional effects. This observation is particularly exciting as it provides mechanistic insight into OA susceptibility. Furthermore, this knowledge reveals avenues for attenuating the negative effect of risk-conferring alleles by exposing the epigenome as an exploitable target for therapeutic intervention in OA.

Key points

  • Genome-wide association studies have uncovered a large number of novel osteoarthritis (OA) genetic risk loci in the past decade.

  • The vast majority of these risk loci map to non-coding regions of the genome and are predicted to increase disease risk by modulating the expression of target genes.

  • Many of these risk loci map close to or correlate with epigenetic mediators.

  • Epigenetic features and mediators therefore represent a mechanistic link between OA genetic risk factors and the onset or progression of disease.

  • Emerging genomic technologies, including assay for transposase-accessible chromatin using sequencing (ATAC-seq), genome editing and single-cell analyses, are starting to facilitate the interpretation of these epigenetic effects in OA.

  • Epigenetic features are amenable to modulation and, as such, are potential therapeutic targets.

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Fig. 1: Proposed mechanism of RUNX2 regulation by an OA-associated mQTL.
Fig. 2: Histone modifiers involved in cartilage development and homeostasis.
Fig. 3: Interactions between SOX9, ROCR, miR-140 and RUNX2 during chondrogenesis and articular cartilage homeostasis.
Fig. 4: The CRISPR–Cas9 system: repurposing for epigenome modulation.


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S.J.R. and J.L. acknowledge research support from Versus Arthritis (grant 20771), the Medical Research Council and Versus Arthritis as part of the Centre for Integrated research into Musculoskeletal Ageing (CIMA, grant JXR 10641, MR/P020941/1 and MR/R502182/1), the Ruth and Lionel Jacobson Charitable Trust, the JGW Patterson Foundation and the Newcastle upon Tyne Hospitals NHS Charity. F.B. acknowledges research support from the Canadian Institutes of Health Research (CIHR; application number 332438). D.A.Y. acknowledges research support from the JGW Patterson Foundation and the Dunhill Medical Trust (grant R476/0516).

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Correspondence to John Loughlin.

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Nature Reviews Rheumatology thanks M. Goldring, J. Westendorf and I. Meulenbelt for their contribution to the peer review of this work.

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GWAS Catalog:


ROADMAP epigenomics project:


The Osteoarthritis Initiative:

WashU Epigenome Browser:


Linkage disequilibrium

The non-random association of two alleles within a population. Alleles at multiple variants that are in linkage disequilibrium will frequently be inherited together and comprise haplotypes. Large regions of linkage disequilibrium, known as ‘LD blocks’, can occur when there is a lack of haplotype diversity.

Allelic expression imbalance

An imbalance in the relative amount of mRNA derived from each allele in a heterozygote individual, as measured by the use of a single-nucleotide polymorphism in the coding sequence or untranslated regions of a gene; any deviation from a 1:1 ratio (determined using DNA from the patient) implies that one allele is associated with a higher expression level than the other allele.

Chromatin immunoprecipitation sequencing

(ChIP-seq). A technique using antibodies and DNA sequencing to assess which proteins are binding to a DNA sequence, and/or which protein modifications are occurring, at particular points of the genome or genome wide; this technique can be performed on chromatin isolated from cell lines or cells from patients.


Short sequences of DNA (<1,500 bp) that can ‘activate’ gene expression when bound by transcription factors by enhancing the activity of the gene promoter through physical interactions in cis.


A sequence of DNA that can repress the expression of a gene through the direct binding of proteins that reduce or block transcription, which predominantly occurs through inhibiting the assembly of transcriptional machinery at a gene promoter.

Methylation quantitative trait loci

(mQTLs). Loci at which there is a correlation between the level of DNA methylation at a CpG site and the genotype at a single nucleotide polymorphism (SNP); mQTL assays are typically performed on DNA derived from cells from patients and can target specific CpGs and SNPs or can analyse the whole genome as part of a genome-wide approach, such as with CpG and genotyping arrays.

Topologically associating domain

(TAD). Regions of the genome in which sequences of DNA can physically interact. Individual TADs are insulated by proteins such as CCCTC-binding factor (CTCF) and cohesin. These domains enable the regulation of target genes by their specific enhancers, while preventing the interaction of regulatory elements with genes outside the TAD.

Methylation and expression quantitative trait locus

(meQTL). A locus at which there is a correlation between the level of methylation at a CpG site and the expression of a gene, the latter being measured directly through quantitative reverse transcription PCR (qRT-PCR) or as part of a genome-wide approach, typically RNA sequencing.


A pathology in which the underlying mechanism of disease involves aberrant function of gene enhancers. This pathology can be caused by altered chromatin state, DNA methylation or sequence variations within the enhancer region. Changes to the enhancer activity result in dysregulation of gene expression.

Gene desert

A region of the genome that is devoid of protein-coding genes. These regions have been linked to several vital regulatory functions and might contain many spatiotemporal enhancers of important genes involved in development, such as SOX9.

Droplet digital PCR

A refinement of the conventional PCR method that uses a water–oil emulsion droplet system. Unlike traditional PCR, where a sample is amplified in a single reaction, droplet digital PCR has the benefit of increased precision through mass sample partitioning; the nucleic acid samples are partitioned into thousands of nanolitre-sized droplets, and PCR amplification is carried out within each droplet, ensuring reliable measurements of the DNA sequence being amplified.

Spatial transcriptomics

A technique developed to quantify RNAs in cells without the need to isolate the cells or to homogenize the tissue, enabling investigators to discern spatial differences in gene expression in complex and heterogeneous tissues.

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Rice, S.J., Beier, F., Young, D.A. et al. Interplay between genetics and epigenetics in osteoarthritis. Nat Rev Rheumatol 16, 268–281 (2020).

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