Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease

Clara Sze Man Tang, Hongsheng Gui, Ashish Kapoor, Jeong Hyun Kim, Berta Luzón-Toro, Anna Pelet, Grzegorz Burzynski, Francesca Lantieri, Man Ting So, Courtney Berrios, Hyoung Doo Shin, Raquel M. Fernández, Thuy Linh Le, Joke B.G.M. Verheij, Ivana Matera, Stacey S. Cherny, Priyanka Nandakumar, Hyun Sub Cheong, Guillermo Antiñolo, Jeanne AmielJeong Meen Seo, Dae Yeon Kim, Jung Tak Oh, Stanislas Lyonnet, Salud Borrego, Isabella Ceccherini, Robert M.W. Hofstra, Aravinda Chakravarti, Hyun Young Kim, Pak Chung Sham, Paul K.H. Tam, Maria Mercè Garcia-Barceló

Research output: Contribution to journalArticlepeer-review


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 Asianspecific, 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.

Original languageEnglish (US)
Pages (from-to)5265-5275
Number of pages11
JournalHuman molecular genetics
Issue number23
StatePublished - 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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