Differential methylation of the TRPA1 promoter in pain sensitivity

Jordana T Bell,Tim D Spector,Panos Deloukas,Kirsten Ward ,A Katrina Loomis ,Stephen B Mcmahon ,Matthew N Davies ,Lee M Butcher ,Leonard C Schalkwyk ,Jihua Sun ,Jonathan Mill ,Honglong Wu ,Baohong Zhang ,J Wang ,Sally John ,Frances Williams ,Juliette Harris ,Craig Hyde ,Stephan Beck ,N Li ,Serena Scollen ,Fei Gao

doi:10.1038/ncomms3978

Abstract

Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood. Here we examine genome-wide DNA methylation, first in 50 identical twins discordant for heat pain sensitivity and then in 50 further unrelated individuals. Whole-blood DNA methylation was characterized at 5.2 million loci by MeDIP sequencing and assessed longitudinally to identify differentially methylated regions associated with high or low pain sensitivity (pain DMRs). Nine meta-analysis pain DMRs show robust evidence for association (false discovery rate 5%) with the strongest signal in the pain gene TRPA1 (P=1.2 × 10−13). Several pain DMRs show longitudinal stability consistent with susceptibility effects, have similar methylation levels in the brain and altered expression in the skin. Our approach identifies epigenetic changes in both novel and established candidate genes that provide molecular insights into pain and may generalize to other complex traits.

Highlights

Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood
We obtained DNA methylation sequencing profiles in a discovery sample of 25 MZ twin pairs (50 MZ twins) who were discordant for heat pain sensitivity determined experimentally using quantitative sensory testing (QST) (Supplementary Fig. S1)
To identify differentially methylated regions (DMRs) associated with heat pain sensitivity we performed two separate pain-sensitivity epigenome-wide association studies (EWAS) on the two cohorts

Summary

Introduction

Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood. We examine genome-wide DNA methylation, first in 50 identical twins discordant for heat pain sensitivity and in 50 further unrelated individuals. Wholeblood DNA methylation was characterized at 5.2 million loci by MeDIP sequencing and assessed longitudinally to identify differentially methylated regions associated with high or low pain sensitivity (pain DMRs). Our approach identifies epigenetic changes in both novel and established candidate genes that provide molecular insights into pain and may generalize to other complex traits. Recent EWAS of DNA methylation differences in disease-discordant monozygotic (MZ) twins have identified potentially differentially methylated regions (DMRs) in several complex diseases, ranging from diabetes to schizophrenia[14,15,16]. We performed detailed genome-wide analyses of DNA methylation and identified modest but consistent and significant DNA methylation changes associated with pain sensitivity, with implications for epigenetic studies of other complex traits. We thereby obtained MA pain DMRs (MAPDMRs) that were strongly supported by both cohorts and further investigated

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