title: Association Analysis of SLC6A20 Polymorphisms With Hirschsprung Disease.
abstract: OBJECTIVE
  Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder, which is caused by no neuronal ganglion cells in part or all of distal gastrointestinal tract. Recently, our genome-wide association study has identified solute carrier family 6, proline IMINO transporter, member 20 (SLC6A20) as one of the potential risk factors for HSCR development. This study performed a replication study for the association of SLC6A20 polymorphisms with HSCR and an extended analysis to investigate further associations for subgroups and haplotypes.
  
  
  METHODS
  For the replication study, a total of 40 single nucleotide polymorphisms (SNPs) of SLC6A20 were genotyped in 187 HSCR subjects composed of 121 short-segment HSCR, 45 long-segment HSCR (L-HSCR), 21 total colonic aganglionosis, and 283 unaffected controls. Imputation was performed using genotype data from our genome-wide association study and this replication study.
  
  
  RESULTS
  Imputed meta-analysis revealed that 13 SLC6A20 SNPs (minimum P = 0.0002 at rs6770261) were significantly associated with HSCR even after correction for multiple comparisons using false discovery rate (FDR) (minimum PFDR =  .005). In further subgroup analysis, SLC6A20 polymorphisms appeared to have increased associations with L-HSCR. Moreover, haplotype analysis also showed significant associations between 2 haplotypes (BL3_ht2 and BL4_ht2) and HSCR susceptibility (PFDR <  .05).
  
  
  CONCLUSIONS
  Although further replications and functional evaluations are required, our results suggest that SLC6A20 may have roles in HSCR development and in the extent of aganglionic segment during enteric nervous system development.
authors.affiliation: †Department of Pediatric Surgery, Severance Children's Hospital, Yonsei University College of Medicine ‡Division of Pediatric Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine §Department of Pediatric Surgery, Asan Medical Center, University of Ulsan College of Medicine ||Department of Pediatric Surgery, Seoul National University Children's Hospital ¶Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Gyeonggi #Department of Genetic Epidemiology, SNP Genetics, Inc **Department of Physiology, College of Medicine, Hanyang University ††Research Institute for Basic Science, Sogang University, Seoul, Republic of Korea.
authors.forename: Jin Sol
authors.initials: JS
authors.lastname: Lee
authors.forename: Jung-Tak
authors.initials: JT
authors.lastname: Oh
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Jeong-Meen
authors.initials: JM
authors.lastname: Seo
authors.forename: Dae-Yeon
authors.initials: DY
authors.lastname: Kim
authors.forename: Kwi-Won
authors.initials: KW
authors.lastname: Park
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Kyuwhan
authors.initials: K
authors.lastname: Jung
authors.forename: Byung Lae
authors.initials: BL
authors.lastname: Park
authors.forename: InSong
authors.initials: I
authors.lastname: Koh
authors.forename: Hyoung Doo
authors.initials: HD
authors.lastname: Shin
mesh_terms: D016022:Case-Control Studies; D004261:DNA Replication; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D026901:Membrane Transport Proteins; C431703:SLC6A20 protein, human