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Discovery and analysis of methylation quantitative trait loci (mQTLs) mapping to novel osteoarthritis genetic risk signals

Lookup NU author(s): Dr Sarah RiceORCiD, Kat Cheung, Dr Louise Reynard, Professor John LoughlinORCiD



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


OBJECTIVE:Osteoarthritis (OA) is polygenic with over 90 independent genome-wide association loci so far reported. A key next step is the identification of target genes and the molecular mechanisms through which this genetic risk operates. The majority of OA risk-conferring alleles are predicted to act by modulating gene expression. DNA methylation at CpG dinucleotides may be a functional conduit through which this occurs and is detectable by mapping methylation quantitative trait loci, or mQTLs. This approach can therefore provide functional insight into OA risk and will prioritize genes for subsequent investigation. That was our goal, with a focus on the largest set of OA loci yet to be reported.METHOD:We investigated DNA methylation, genotype and RNA sequencing data derived from the cartilage of patients who had undergone arthroplasty and combined this with in silico analyses of expression quantitative trait loci, epigenomes and chromatin interactions.RESULTS:We investigated 42 OA risk loci and in ten of these we identified 24 CpGs in which methylation correlated with genotype (false discovery rate P-values ranging from 0.049 to 1.73x10-25). In silico analyses of these mQTLs prioritised genes and regulatory elements at the majority of the ten loci, with COLGALT2 (encoding a collagen galactosyltransferase), COL11A2 (encoding a polypeptide chain of type XI collagen) and WWP2 (encoding a ubiquitin ligase active during chondrogenesis) emerging as particularly compelling target genes.CONCLUSION:We have highlighted the pivotal role of DNA methylation as a link between genetic risk and OA and prioritized genes for further investigation.

Publication metadata

Author(s): Rice SJ, Cheung K, Reynard LN, Loughlin J

Publication type: Article

Publication status: Published

Journal: Osteoarthritis and Cartilage

Year: 2019

Volume: 27

Issue: 10

Pages: 1545-1556

Print publication date: 01/10/2019

Online publication date: 05/06/2019

Acceptance date: 24/05/2019

Date deposited: 10/06/2019

ISSN (print): 1522-9653

ISSN (electronic): 1063-4584

Publisher: Elsevier


DOI: 10.1016/j.joca.2019.05.017

PubMed id: 31173883


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Funder referenceFunder name
20771VERSUS Arthritis (formerly Arthritis Research UK)
JXR 10641