S J Rice1, K Cheung2, L N Reynard3, J Loughlin4. 1. Newcastle University, Institute of Genetic Medicine, Newcastle upon Tyne, UK. Electronic address: sarah.rice@newcastle.ac.uk. 2. Newcastle University, Institute of Genetic Medicine, Newcastle upon Tyne, UK; Newcastle University, Bioinformatics Support Unit, Newcastle upon Tyne, UK. Electronic address: kat.cheung@newcastle.ac.uk. 3. Newcastle University, Institute of Genetic Medicine, Newcastle upon Tyne, UK. Electronic address: louise.reynard@newcastle.ac.uk. 4. Newcastle University, Institute of Genetic Medicine, Newcastle upon Tyne, UK. Electronic address: john.loughlin@newcastle.ac.uk.
Abstract
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 (FDR) 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.
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 (FDR) 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.
Authors: A K Sorial; I M J Hofer; M Tselepi; K Cheung; E Parker; D J Deehan; S J Rice; J Loughlin Journal: Osteoarthritis Cartilage Date: 2020-06-21 Impact factor: 6.576
Authors: Purva Singh; Mengying Wang; Piali Mukherjee; Samantha G Lessard; Tania Pannellini; Camila B Carballo; Scott A Rodeo; Mary B Goldring; Miguel Otero Journal: Sci Rep Date: 2021-10-26 Impact factor: 4.996
Authors: Michael Scherer; Gilles Gasparoni; Souad Rahmouni; Tatiana Shashkova; Marion Arnoux; Edouard Louis; Arina Nostaeva; Diana Avalos; Emmanouil T Dermitzakis; Yurii S Aulchenko; Thomas Lengauer; Paul A Lyons; Michel Georges; Jörn Walter Journal: Epigenetics Chromatin Date: 2021-09-16 Impact factor: 4.954
Authors: Peter Kreitmaier; Matthew Suderman; Lorraine Southam; Rodrigo Coutinho de Almeida; Konstantinos Hatzikotoulas; Ingrid Meulenbelt; Julia Steinberg; Caroline L Relton; J Mark Wilkinson; Eleftheria Zeggini Journal: Am J Hum Genet Date: 2022-06-08 Impact factor: 11.043