TY - JOUR
T1 - Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease
AU - Tang, Clara Sze Man
AU - Gui, Hongsheng
AU - Kapoor, Ashish
AU - Kim, Jeong Hyun
AU - Luzón-Toro, Berta
AU - Pelet, Anna
AU - Burzynski, Grzegorz
AU - Lantieri, Francesca
AU - So, Man Ting
AU - Berrios, Courtney
AU - Shin, Hyoung Doo
AU - Fernández, Raquel M.
AU - Le, Thuy Linh
AU - Verheij, Joke B.G.M.
AU - Matera, Ivana
AU - Cherny, Stacey S.
AU - Nandakumar, Priyanka
AU - Cheong, Hyun Sub
AU - Antiñolo, Guillermo
AU - Amiel, Jeanne
AU - Seo, Jeong Meen
AU - Kim, Dae Yeon
AU - Oh, Jung Tak
AU - Lyonnet, Stanislas
AU - Borrego, Salud
AU - Ceccherini, Isabella
AU - Hofstra, Robert M.W.
AU - Chakravarti, Aravinda
AU - Kim, Hyun Young
AU - Sham, Pak Chung
AU - Tam, Paul K.H.
AU - Garcia-Barceló, Maria Mercè
PY - 2016
Y1 - 2016
N2 - 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=85016038994&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddw333
DO - 10.1093/hmg/ddw333
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AN - SCOPUS:85016038994
SN - 0964-6906
VL - 25
SP - 5265
EP - 5275
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 23
ER -