title: Genome-wide methylation analysis of a large population sample shows neurological pathways involvement in chronic widespread musculoskeletal pain.
abstract: Chronic widespread musculoskeletal pain (CWP), has a considerable heritable component, which remains to be explained. Epigenetic factors may contribute to and account for some of the heritability estimate. We analysed epigenome-wide methylation using MeDIPseq in whole blood DNA from 1708 monozygotic and dizygotic Caucasian twins having CWP prevalence of 19.9%. Longitudinally stable methylation bins (lsBINs), were established by testing repeated measurements conducted ≥3 years apart, n = 292. DNA methylation variation at lsBINs was tested for association with CWP in a discovery set of 50 monozygotic twin pairs discordant for CWP, and in an independent dataset (n = 1608 twins), and the results from the 2 samples were combined using Fisher method. Functional interpretation of the most associated signals was based on functional genomic annotations, gene ontology, and pathway analyses. Of 723,029 signals identified as lsBINs, 26,399 lsBINs demonstrated the same direction of association in both discovery and replication datasets at nominal significance (P ≤ 0.05). In the combined analysis across 1708 individuals, whereas no lsBINs showed genome-wide significance (P < 10-8), 24 signals reached p≤9E-5, and these included association signals mapping in or near to IL17A, ADIPOR2, and TNFRSF13B. Bioinformatics analyses of the associated methylation bins showed enrichment for neurological pathways in CWP. We estimate that the variance explained by epigenetic factors in CWP is 6%. This, the largest study to date of DNA methylation in CWP, points towards epigenetic modification of neurological pathways in CWP and provides proof of principle of this method in teasing apart the complex risk factors for CWP.
authors.affiliation: aDepartment of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom bDepartment of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel cBeiging Genomic Institute-Shenzhen, Shenzhen, China dSchool of Medicine, University of East Anglia, Norwich, United Kingdom.
authors.forename: Gregory
authors.initials: G
authors.lastname: Livshits
authors.forename: Ida
authors.initials: I
authors.lastname: Malkin
authors.forename: Maxim B
authors.initials: MB
authors.lastname: Freidin
authors.forename: Yudong
authors.initials: Y
authors.lastname: Xia
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Alex
authors.initials: A
authors.lastname: MacGregor
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.forename: Frances M K
authors.initials: FMK
authors.lastname: Williams
mesh_terms: D002874:Chromosome Mapping; D059350:Chronic Pain / Q000453:epidemiology* / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D059352:Musculoskeletal Pain / Q000453:epidemiology* / Q000235:genetics*; D009434:Neural Pathways / Q000503:physiopathology*