Severity of Idiopathic Scoliosis Is Associated with Differential Methylation: An Epigenome-Wide Association Study of Monozygotic Twins with Idiopathic Scoliosis.

Patrick Carry,Parvaneh Ebrahimi,Cambria Wethey,George Trahan,Kristina Åkesson,Fiona Mcguigan,Lauren Vanderlinden,Elizabeth Terhune,Nancy Hadley-Miller

doi:10.3390/genes12081191

Abstract

Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS.

Highlights

We identified 13 priority regions based on the discordant Differentially methylated region (DMR) analysis and 8 priority candidate regions based on the severity DMR
We identified a single cytosine phosphate guanine (CpG) site where methylation variability was different between discordant MZ twins and identified CpG sites where increasing curve severity was more often associated with hypomethylation
DNA methylation markers may provide value as a prognostic tool for predicting both the initiation and progression of this disorder and may aid in the identification of homogenous subgroups of individuals allowing for more personalized treatment algorithms

Summary

Introduction

Adolescent idiopathic scoliosis (IS) is a three-dimensional spinal deformity affecting 1–3% of otherwise normal prepubescent and adolescent individuals [1,2]. Conservative treatment, and surgical care in the case of progressive curvatures impose significant personal, familial, financial, and societal costs across the lifetime of affected individuals. It has been shown to have a strong familial component [3] with a sibling recurrence risk of 18%, and heritability estimates of approximately 87.5% [4,5,6]

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