title: A genome-wide association study identifies potential susceptibility loci for Hirschsprung disease.
abstract: Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder characterized by the absence of intramural nervous plexuses along variable lengths of the hindgut. Although RET is a well-established risk factor, a recent genome-wide association study (GWAS) of HSCR has identified NRG1 as an additional susceptibility locus. To discover additional risk loci, we performed a GWAS of 123 sporadic HSCR patients and 432 unaffected controls using a large-scale platform with coverage of over 1 million polymorphic markers. The result was that our study replicated the findings of RET-CSGALNACT2-RASGEF1A genomic region (rawP = 5.69×10(-19) before a Bonferroni correction; corrP = 4.31×10(-13) after a Bonferroni correction) and NRG1 as susceptibility loci. In addition, this study identified SLC6A20 (adjP = 2.71×10(-6)), RORA (adjP = 1.26×10(-5)), and ABCC9 (adjP = 1.86×10(-5)) as new potential susceptibility loci under adjusting the already known loci on the RET-CSGALNACT2-RASGEF1A and NRG1 regions, although none of the SNPs in these genes passed the Bonferroni correction. In further subgroup analysis, the RET-CSGALNACT2-RASGEF1A genomic region was observed to have different significance levels among subgroups: short-segment (S-HSCR, corrP = 1.71×10(-5)), long-segment (L-HSCR, corrP = 6.66×10(-4)), and total colonic aganglionosis (TCA, corrP>0.05). This differential pattern in the significance level suggests that other genomic loci or mechanisms may affect the length of aganglionosis in HSCR subgroups during enteric nervous system (ENS) development. Although functional evaluations are needed, our findings might facilitate improved understanding of the mechanisms of HSCR pathogenesis.
authors.affiliation: Research Institute for Basic Science, Sogang University, Seoul, Republic of Korea; Department of Life Science, Sogang University, Seoul, Republic of Korea.
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Republic of Korea.
authors.forename: Hyun Sub
authors.initials: HS
authors.lastname: Cheong
authors.affiliation: Department of Computer Science, University of California Los Angeles, Los Angeles, California, United States of America.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Sul
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jeong-Meen
authors.initials: JM
authors.lastname: Seo
authors.affiliation: Department of Pediatric Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Dae-Yeon
authors.initials: DY
authors.lastname: Kim
authors.affiliation: Department of Pediatric Surgery, Severance Children's Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung-Tak
authors.initials: JT
authors.lastname: Oh
authors.affiliation: Department of Pediatric Surgery, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Kwi-Won
authors.initials: KW
authors.lastname: Park
authors.affiliation: Department of Pediatric Surgery, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Division of Pediatric Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Soo-Min
authors.initials: SM
authors.lastname: Jung
authors.affiliation: Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Republic of Korea.
authors.forename: Kyuwhan
authors.initials: K
authors.lastname: Jung
authors.affiliation: Department of Surgery, Konkuk University Medical Center, Seoul, Republic of Korea.
authors.forename: Min Jeng
authors.initials: MJ
authors.lastname: Cho
authors.affiliation: Laboratory of Translational Genomics, Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Joon Seol
authors.initials: JS
authors.lastname: Bae
authors.affiliation: Research Institute for Basic Science, Sogang University, Seoul, Republic of Korea; Department of Life Science, Sogang University, Seoul, Republic of Korea; Department of Genetic Epidemiology, SNP Genetics, Inc., Seoul, Republic of Korea.
authors.forename: Hyoung Doo
authors.initials: HD
authors.lastname: Shin
mesh_terms: D002877:Chromosomes, Human / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics