Whole-Genome Methylation Analysis of Phenotype Discordant Monozygotic Twins Reveals Novel Epigenetic Perturbation Contributing to the Pathogenesis of Adolescent Idiopathic Scoliosis.

Yuzhi Zuo,Lianlei Wang,Sen Zhao,Sen Liu,Zihui Yan,Xinyu Wang,Mao Lin,Yanxue Zhao,Nan Wu,Jianguo Zhang,Zhihong Wu,Gang Liu,Jianxiong Shen,Yipeng Wang,Guixing Qiu,Yuchen Niu,Xinzhuang Yang

doi:10.3389/fbioe.2019.00364

Abstract

Background: Adolescent idiopathic scoliosis (AIS) is a complex disease affecting a large number of teenagers, especially in female. This study reveals novel epigenetic perturbation to the pathogenesis of AIS.Methods: A female monozygotic (MZ) twin pair discordant for AIS were examined for whole-exome sequencing and epigenome difference. Sets of differentially methylated regions (DMRs) were validated using MethylTarget™ method in 20 AIS female patients and 20 healthy female controls.Results: Few exome difference but several potential DMRs were found between the MZ twins. We identified 313 hypermethylated DMRs and 397 hypomethylated DMRs, respectively. Most of them were enriched in the MAPK and PI3K-Akt signaling pathway, which may contribute to the discordance of AIS. Several DMRs related to scoliosis genes were tested, and the NDN: TSS-DMR (chr15:23932133-23932304, hg19) was confirmed in additional samples. The methylation level of this DMR was significantly higher in the AIS group than in the control group (p = 0.04).Conclusions: We described the epigenome difference in an AIS female discordant MZ twin pair using Whole Genome Bisulfite Sequencing (WGBS). The NDN: TSS-DMR had higher methylation level in female AIS, which can help elucidate the potential etiology of AIS.

Highlights

Adolescent idiopathic scoliosis (AIS) is a 3-dimensional spinal deformity affecting 1–3% of children in the world (Yawn et al, 1999)
We found three de novo single nucleotide variant (SNV), but the healthy twin sister had these SNVs, indicating that pathogenesis of AIS may not be on account of these variants
The previous study showed that MAPK signaling pathway and PI3K-Akt signaling pathway were downregulated in bone marrow mesenchymal stem cells (BM-MSCs) of AIS, which may contribute to the AIS initiation and development (Zhuang et al, 2016)

Summary

Introduction

Adolescent idiopathic scoliosis (AIS) is a 3-dimensional spinal deformity affecting 1–3% of children in the world (Yawn et al, 1999). Previous studies showed that genetic factors from single nucleotide variant (SNV) to copy number variants (CNV), played a pivotal role in the development of AIS (Kesling and Reinker, 1997; Li et al, 2016; Gao et al, 2017). Other studies illustrated the association between CNV and AIS (Buchan et al, 2014b). All of those genetic factors can only explain the etiology of 2–7.6% of AIS (Buchan et al, 2014a; Ikegawa, 2016). Adolescent idiopathic scoliosis (AIS) is a complex disease affecting a large number of teenagers, especially in female. This study reveals novel epigenetic perturbation to the pathogenesis of AIS

Methods

Results

Conclusion