Toggle Main Menu Toggle Search

Open Access padlockePrints

Multi‐Tissue Epigenetic and Gene Expression Analysis Combined With Epigenome Modulation Identifies RWDD2B as a Target of Osteoarthritis Susceptibility

Lookup NU author(s): Dr Sarah Rice, Dr Sami Anjum, Professor David Deehan, Professor John Loughlin

Downloads


Licence

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


Abstract

Objective: Osteoarthritis (OA) is polygenic with over 90 risk loci currently mapped, including at the single nucleotide polymorphism (SNP) rs6516886. Previous analysis of OA patient cartilage DNA identified six CpG dinucleotides whose methylation levels correlated with rs6516886 genotype, forming methylation quantitative trait loci (mQTLs). Here we investigate these mQTLs, and map expression quantitative trait loci (eQTLs), across joint tissues to prioritise a gene as a target of the rs6516886 association effect.Methods: Nucleic acids were extracted from cartilage, fat pad, synovium and peripheral blood of OA patients. Methylation of CpGs and allelic expression imbalance of potential target genes were assessed by pyrosequencing. A chondrocyte cell line expressing dCas9-TET1 was used to directly alter CpG methylation levels, with effects on gene expression quantified by PCR.Results: Multiple mQTLs were detected, with effects strongest in joint tissues and with methylation at CpG cg20220242 correlating most significantly with rs6516886 genotype. cg20220242 is located upstream of RWDD2B. Significant rs6516886 eQTLs were observed for this gene, with the OA risk-conferring allele of rs6516886 correlating with reduced expression. CpG methylation also correlated with allelic expression of RWDD2B, forming methylation-expression QTLs (meQTLs). dCas9-TET1 reduction in the methylation of cg20220242 increased expression of RWDD2B.Conclusions: The rs6516886 association signal is a multi-tissue meQTL involving cg20220242 and acting on RWDD2B. Modulating CpG methylation reverses the impact of the risk allele. RWDD2B codes for a protein for which little is currently known. Its further analysis as a target of OA genetic risk will provide novel insight into this complex disease.


Publication metadata

Author(s): Parker E, Hofer IMJ, Rice SJ, Earl L, Anjum SA, Deehan DJ, Loughlin J

Publication type: Article

Publication status: Published

Journal: Arthritis and Rheumatology

Year: 2021

Volume: 73

Issue: 1

Pages: 100-109

Print publication date: 01/01/2021

Online publication date: 04/08/2020

Acceptance date: 17/07/2020

Date deposited: 06/08/2020

ISSN (print): 2326-5191

ISSN (electronic): 2326-5205

Publisher: John Wiley & Sons, Inc.

URL: https://doi.org/10.1002/art.41473

DOI: 10.1002/art.41473

PubMed id: 32755071


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share