title: Exome-Wide Association Study Identified New Risk Loci for Hirschsprung's Disease.
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 < 10-4in the single-variant analysis while ten genes were also associated with HSCR at P < 10-4in 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.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, 210008, China.
authors.forename: Weibing
authors.initials: W
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, 210008, China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Key Laboratory of Modern Toxicology, Ministry of Education, Nanjing Medical University, Nanjing, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Guangfu
authors.initials: G
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, 210008, China.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated Nanjing Medical University, Nanjing, 210008, China.
authors.forename: Hairong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.|Key Laboratory of Modern Toxicology, Ministry of Education, Nanjing Medical University, Nanjing, China.
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. zhibin_hu@njmu.edu.cn.|Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China. zhibin_hu@njmu.edu.cn.
authors.forename: Zhibing
authors.initials: Z
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. yankaixia@njmu.edu.cn.|Key Laboratory of Modern Toxicology, Ministry of Education, Nanjing Medical University, Nanjing, China. yankaixia@njmu.edu.cn.
authors.forename: Yankai
authors.initials: Y
authors.lastname: Xia
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059472:Exome / Q000235:genetics*; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study; D006627:Hirschsprung Disease / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
keywords: Exome-wide; Hirschsprung’s disease; MAF; Migration; Proliferation