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Molecular Neurobiology

, Volume 54, Issue 3, pp 1777–1785 | Cite as

Exome-Wide Association Study Identified New Risk Loci for Hirschsprung’s Disease

  • Weibing Tang
  • Junwei Tang
  • Yang Zhao
  • Yufeng Qin
  • Guangfu Jin
  • Xiaoqun Xu
  • Hairong Zhu
  • Hongbing Shen
  • Xinru Wang
  • Zhibing HuEmail author
  • Yankai XiaEmail author
Article

Abstract

Hirschsprung disease (HSCR) is a rare congenital disease caused by impaired proliferation and migration of neural crest cells. In this study, we aimed to investigate the genetic loci involved in the pathogenesis of HSCR. The exome-wide scan was performed to screen the genetic variants with minor allele frequency (MAF) < 0.05 in exonic regions. Candidate mutation type and the wild type were overexpressed to investigate the affection on cell proliferation and migration. We found that ten variants were associated with HSCR at P < 10−4 in the single-variant analysis while ten genes were also associated with HSCR at P < 10−4 in the optimized sequence kernel association test (SKAT-O) test analysis. Among these SNPs, the missense variants catechol-O-methyltransferase (COMT) (rs6267) and armadillo repeat gene deleted in velocardiofacial syndrome (ARVCF) (rs80068543) indicated an ectopic expression in colon tissues of HSCR patients. The Ala72Ser variant in COMT induced proliferation suppression through NOTCH signal pathway, while the ARVCF affected cell migration via the downregulating of RHOA and ROC. In conclusion, this exome array study identified the COMT and ARVCF missense coding variants as candidate loci for HSCR. The finding implies the abnormal variant of COMT and ARVCF may account for the pathogenesis of HSCR.

Keywords

Hirschsprung’s disease Exome-wide MAF Proliferation Migration 

Notes

Acknowledgments

We thank Dr. Weiwei Jiang, Xiaofeng Lv, and Changgui Lu (Nanjing Children’s Hospital Affiliated to Nanjing Medical University) for sample collection. Grant support: Natural Science Foundation of China, Grant Number 81370473; Natural Science Foundation of Jiangsu Province of China, Grant Number BK20131388; Scientific Research Project of Jiangsu Provincial Department of Health, Grant Number H201342; New Century Excellent Talents of MOE, Grant Number NCET-13-0870; Priority Academic Program Development of Jiangsu Higher Education Institutions SKLRM-KF-1104; Nanjing Science and Technique Development Foundation (201108010); and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Compliance with Ethical Standards

Conflict of Interest

None

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Weibing Tang
    • 1
    • 2
  • Junwei Tang
    • 1
    • 2
  • Yang Zhao
    • 1
    • 3
  • Yufeng Qin
    • 1
    • 4
  • Guangfu Jin
    • 1
    • 3
  • Xiaoqun Xu
    • 1
    • 2
  • Hairong Zhu
    • 2
  • Hongbing Shen
    • 1
    • 3
  • Xinru Wang
    • 1
    • 4
  • Zhibing Hu
    • 1
    • 3
    Email author
  • Yankai Xia
    • 1
    • 4
    Email author
  1. 1.State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public HealthNanjing Medical UniversityNanjingChina
  2. 2.Department of Pediatric SurgeryNanjing Children’s Hospital Affiliated Nanjing Medical UniversityNanjingChina
  3. 3.Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public HealthNanjing Medical UniversityNanjingChina
  4. 4.Key Laboratory of Modern Toxicology, Ministry of EducationNanjing Medical UniversityNanjingChina

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