Potential association between TSGA13 variants and risk of total colonic aganglionosis in Hirschsprung disease

Hirschsprung disease (HSCR) is a congenital rare disorder and a kind of developmental neuropathies, characterized by the lack of enteric neurons in variable segments of distal bowel. Our recent genome-wide association study identified a variant (rs13223150) of testis-specific A13 (TSGA13) as a potential risk locus for total colonic aganglionosis (TCA) in HSCR. The aim of this study was to identify the impact of the variant (rs13223150) and potential association of genetic variations of TSGA13 with TCA in HSCR. This study performed a fine mapping and extended analyses in Korean population. A total of 9 single nucleotide polymorphisms (SNPs) of TSGA13 were genotyped in a larger HSCR cohort (187 HSCR patients and 283 unaffected controls), and extended genetic analyses using various genetic modelling, haplotype, and combined analyses were performed. The rs13223150_A allele showed a significant association with TCA (P = 0.003), even after correcting for multiple testing (Pcorr = 0.02). One haplotype (BL1_ht1, G-A-C-C) including rs13223150 also showed a significant association with TCA (P = 0.002, Pcorr = 0.01). Further combined imputation analysis indicated that several single nucleotide polymorphisms of TSGA13 were significantly associated with TCA in HSCR. Although replications in other population cohorts and functional evaluations are needed, our results suggest that TSGA13 genetic variants may affect TCA in HSCR and/or the extent of aganglionosis during enteric nervous system development. •Our previous GWAS has identified TSGA13 as a potential susceptible locus in total colonic aganglionosis (TCA) of HSCR.•This study performed additional fine mapping of TSGA13 variants and extended genetic analyses.•TSGA13 genetic variants were found to be significantly associated with TCA in HSCR.•TSGA13 genetic variants were found to be significantly associated with TCA in HSCR. TSGA13 may affect TCA in HSCR and/or the extent of aganglionosis during enteric nervous system development.