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

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

doi:10.3389/fbioe.2019.00364

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

Front Bioeng Biotechnol. 2019 Dec 10:7:364. doi: 10.3389/fbioe.2019.00364. eCollection 2019.

Authors

Gang Liu^{1

2}, Lianlei Wang^{1

2}, Xinyu Wang³, Zihui Yan^{1

2}, Xinzhuang Yang^{2

4}, Mao Lin^{1

2}, Sen Liu^{1

2}, Yuzhi Zuo^{1

2}, Yuchen Niu^{2

4}, Sen Zhao^{1

2}, Yanxue Zhao^{1

2}, Jianguo Zhang^{1

2

5}, Jianxiong Shen^{1

2

5}, Yipeng Wang^{1

2

5}, Guixing Qiu^{1

2

5}, Zhihong Wu^{2

4

5}, Nan Wu^{1

2

5}

Affiliations

¹ Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
² Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.
³ Institute of Biomedical Big Data, Wenzhou Medical University, Wenzhou, China.
⁴ Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
⁵ Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China.

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.

Keywords: DNA methylation; adolescent idiopathic scoliosis (AIS); monozygotic twins; whole exome sequencing (WES); whole genome bisulfite sequencing (WGBS).