Association Analysis of SLC6A20 Polymorphisms With Hirschsprung Disease

Purpose: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 P-FDR=0.005). 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 (P-FDR<0.05).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.