RT Journal Article
T1 Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease.
A1 Tang, Clara Sze-Man
A1 Gui, Hongsheng
A1 Kapoor, Ashish
A1 Kim, Jeong-Hyun
A1 Luzón-Toro, Berta
A1 Pelet, Anna
A1 Burzynski, Grzegorz
A1 Lantieri, Francesca
A1 So, Man-Ting
A1 Berrios, Courtney
A1 Shin, Hyoung Doo
A1 Fernández, Raquel M
A1 Le, Thuy-Linh
A1 Verheij, Joke B G M
A1 Matera, Ivana
A1 Cherny, Stacey S
A1 Nandakumar, Priyanka
A1 Cheong, Hyun Sub
A1 Antiñolo, Guillermo
A1 Amiel, Jeanne
A1 Seo, Jeong-Meen
A1 Kim, Dae-Yeon
A1 Oh, Jung-Tak
A1 Lyonnet, Stanislas
A1 Borrego, Salud
A1 Ceccherini, Isabella
A1 Hofstra, Robert M W
A1 Chakravarti, Aravinda
A1 Kim, Hyun-Young
A1 Sham, Pak Chung
A1 Tam, Paul K H
A1 Garcia-Barceló, Maria-Mercè
AB Hirschsprung disease (HSCR) is the most common cause of neonatal intestinal obstruction. It is characterized by the absence of ganglia in the nerve plexuses of the lower gastrointestinal tract. So far, three common disease-susceptibility variants at the RET, SEMA3 and NRG1 loci have been detected through genome-wide association studies (GWAS) in Europeans and Asians to understand its genetic etiologies. Here we present a trans-ethnic meta-analysis of 507 HSCR cases and 1191 controls, combining all published GWAS results on HSCR to fine-map these loci and narrow down the putatively causal variants to 99% credible sets. We also demonstrate that the effects of RET and NRG1 are universal across European and Asian ancestries. In contrast, we detected a European-specific association of a low-frequency variant, rs80227144, in SEMA3 [odds ratio (OR) = 5.2, P = 4.7 × 10-10]. Conditional analyses on the lead SNPs revealed a secondary association signal, corresponding to an Asian-specific, low-frequency missense variant encoding RET p.Asp489Asn (rs9282834, conditional OR = 20.3, conditional P = 4.1 × 10-14). When in trans with the RET intron 1 enhancer risk allele, rs9282834 increases the risk of HSCR from 1.1 to 26.7. Overall, our study provides further insights into the genetic architecture of HSCR and has profound implications for future study designs.
YR 2016
FD 2016
LK http://hdl.handle.net/10668/10504
UL http://hdl.handle.net/10668/10504
LA en
DS RISalud
RD Apr 3, 2025