title: Methylation quantitative trait locus analysis of osteoarthritis links epigenetics with genetic risk.
abstract: Osteoarthritis (OA) is a common, painful and debilitating disease of articulating joints resulting from the age-associated loss of cartilage. Well-powered genetic studies have identified a number of DNA polymorphisms that are associated with OA susceptibility. Like most complex trait loci, these OA loci are thought to influence disease susceptibility through the regulation of gene expression, so-called expression quantitative loci, or eQTLs. One mechanism through which eQTLs act is epigenetic, by modulating DNA methylation. In such cases, there are quantitative differences in DNA methylation between the two alleles of the causal polymorphism, with the association signal referred to as a methylation quantitative trait locus, or meQTL. In this study, we aimed to investigate whether the OA susceptibility loci identified to date are functioning as meQTLs by integrating genotype data with whole genome methylation data of cartilage DNA. We investigated potential genotype-methylation correlations within a 1.0-1.5 Mb region surrounding each of 16 OA-associated single-nucleotide polymorphisms (SNPs) in 99 cartilage samples and identified four that function as meQTLs. Three of these replicated in an additional cohort of up to 62 OA patients. These observations suggest that OA susceptibility loci regulate the level of DNA methylation in cis and provide a mechanistic explanation as to how these loci impact upon OA susceptibility, further increasing our understanding of the role of genetics and epigenetics in this common disease.
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine and.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rushton
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine and.
authors.forename: Louise N
authors.initials: LN
authors.lastname: Reynard
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine and.
authors.forename: David A
authors.initials: DA
authors.lastname: Young
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine and.
authors.forename: Colin
authors.initials: C
authors.lastname: Shepherd
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine and.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Aubourg
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine and.
authors.forename: Fiona
authors.initials: F
authors.lastname: Gee
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK and.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Darlay
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine and, Freeman Hospital, High Heaton, Newcastle upon Tyne NE7 7DN, UK.
authors.forename: David
authors.initials: D
authors.lastname: Deehan
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK and.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine and, john.loughlin@ncl.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Loughlin
mesh_terms: D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D010003:Osteoarthritis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics